Concomitant administration of glucocorticoid receptor modulators and CYP3A inhibitors

ABSTRACT

Applicant provides methods of treating diseases including Cushing&#39;s syndrome and hormone-sensitive cancers by concomitant administration of a glucocorticoid receptor antagonist (GRA) and steroidogenesis inhibitors, and by concomitant administration of a GRA and CYP3A inhibitors. Applicant provides methods of treating diseases including Cushing&#39;s syndrome and hormone-sensitive cancers by concomitant administration of mifepristone and ketoconazole. 
     Subjects treated with CYP3A inhibitors or steroidogenesis inhibitors may suffer from toxicity or other serious adverse reactions; concomitant administration of other drugs would be expected to increase the risk of such toxicity and adverse reactions. Applicant has surprisingly found that GRAs may be administered to subjects receiving CYP3A inhibitors or steroidogenesis inhibitors such as ketoconazole without increasing risk adverse reactions; for example, Applicant has found that mifepristone may be concomitantly administered with ketoconazole (a CYP3A inhibitor and a steroidogenesis inhibitor), providing safe concomitant administration of the GRA and ketoconazole. In embodiments, the GRA dose may be reduced.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.15/627,359, filed Jun. 19, 2017, which claims priority to U.S.Provisional Application Ser. No. 62/465,772, filed Mar. 1, 2017, andU.S. Provisional Application Ser. No. 62/466,867, filed Mar. 3, 2017,the entire contents of both of which applications are herebyincorporated by reference in their entireties.

BACKGROUND

Steroid molecules, such as steroid hormones, play an important role inbodily functions and in bodily responses to infectious and otherdiseases, and to the environment. Many steroid molecules are synthesizedin the body, or are produced from molecules consumed in the diet.Steroid molecules which act as hormones in the body include estrogen,progesterone, testosterone, and cortisol. Some steroid molecules havemedicinal effects. Inhibition of steroid synthesis or metabolism can beuseful in the treatment of some disorders.

Cortisol, a steroid molecule, plays an important role in many bodilyfunctions. Cortisol exerts effects by binding to cortisol receptors,which are present in most tissues in the body. However, dysregulation ofcortisol may have adverse effects on a subject. For example, Cushing'ssyndrome, caused by excess levels of cortisol, is characterized bysymptoms including elevated blood pressure, elevated blood glucose,increased weight, increased mid-section perimeter, other pre-diabeticsymptom, a “moon-face” facial appearance, immune suppression, thin skin,acne, depression, hirsutism, and other symptoms. Clinical manifestationsof Cushing's syndrome include abnormalities in glucose control,requirement for anti-diabetic medication, abnormalities in insulinlevel, abnormal psychiatric symptoms, cushingoid appearance, acne,hirsutism, and increased or excessive body weight, and other symptoms.

One effective treatment of cortisol dysregulation is to block thebinding of cortisol to cortisol receptors, or to block the effect ofcortisol binding to cortisol receptors. Mifepristone binds to cortisolreceptors, and acts to block such binding and to block the effect ofcortisol on tissues. Mifepristone is11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(1-propynyl)-estra-4,9-dien-3-one).

Another effective treatment of cortisol dysregulation is to reduce thesynthesis of cortisol, e.g., by reducing or blocking steroid synthesis.A “steroidogenesis inhibitor” is a compound which reduces or blocks thesynthesis of steroid molecules (including, e.g., cortisol) whenadministered to a subject. Steroidogenesis inhibitors include, forexample, ketoconazole, metyrapone, etomidate, and other drugs.

Many enzymes are involved in steroid synthesis and in steroidmetabolism, including cytochrome P450 enzymes, encoded by CAT genes.Inhibiting steroid synthesis may lower the levels of steroids,including, e.g., cortisol, in the blood. For example, CYP3A enzymes playimportant roles in the synthesis of steroid hormones such as cortisol.

However, many drugs inhibit the levels or actions of CYP3A gene products(termed “inhibit CYP3A”). The following drugs inhibit CYP3A:ketoconazole, itraconazole, fluconazole, cimetidine, nefazodone,ritonavir, nelfinavir, indinavir, atazanavir, amprenavir, fosamprenavir,boceprevir, clarithromycin, conivaptan, lopinavir, posaconazole,saquinavir, telaprevir, telithromycin, and voriconazole, among manydrugs which inhibit CYP3A. For example, the following drugs stronglyinhibit CYP3A (i.e., increase AUC (area under the concentration-timecurve) by 10-fold or greater of sensitive index substrates), eitheralone or in combination with other drugs: boceprevir, cobicistat,conivaptan, danoprevir and ritonavir, elvitegravir and ritonavir,indinavir, ritonavir, itraconazole, ketoconazole, lopinavir,paritaprevir, ombitasvir, dasabuvir, posaconazole, saquinavir,telaprevir, tipranavir, troleandomycin, and voriconazole.

Ketoconazole is an exemplary and an important steroidogenesis inhibitorand is a strong CYP3A inhibitor. Ketoconazole (chemical name:1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)-methyl]-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine)is administered for the treatment of fungal infections; it also affectssteroid metabolism by inhibiting steroidogenesis, and hasanti-glucocorticoid and anti-androgen effects due to its interferencewith enzymatic conversion of cholesterol to hormones such as cortisoland testosterone. Ketoconazole has effects on liver enzymes and thegastrointestinal ((GI) tract, among other effects (Fleseriu andCastinetti, Pituitary 19:643-653 (2016)).

Ketoconazole inhibits steroid synthesis and is thus useful in thetreatment Cushing's syndrome; in the treatment of prostate cancer andother androgen-sensitive cancers; to reduce estrogen or progesteroneproduction (e.g., in patients with hormone-sensitive cancers such asbreast cancer and ovarian cancer); and in other treatments.

A drug such as ketoconazole is typically metabolized and excreted by asubject over time following administration. An effective dose isdetermined based on the expected amounts of metabolism and excretion ofthe drug. Changes in the amounts or rates of metabolism and/or excretionof a drug will affect the dose required, and may make an otherwise safedose, if metabolism or excretion changes, into either a less, orineffective dose, or a more effective or even toxic dose.

However, although sometimes clinically useful, ketoconazole may haveadverse, including seriously toxic, effects (Fleseriu and Castinetti,Pituitary 19:643-653 (2016)). The U.S. Food and Drug Administrationissued a Drug Safety Communication (Jul. 26, 2013 Safety Announcementregarding Nizoral® (ketoconazole)) warning of potentially fatal liverdamage associated with oral ketoconazole treatment and warning of therisk of adrenal insufficiency, also a potentially fatal disorder. TheSafety Announcement warned: “Nizoral tablets can cause liver injury,which may potentially result in liver transplantation or death.” TheSafety Announcement further stated: “Nizoral tablets may interact withother drugs a patient is taking and can result in serious andpotentially life-threatening outcomes, such as heart rhythm problems.”Thus, ketoconazole can be quite toxic if administered in excessiveamounts, or if it is administered to sensitive individuals, particularlywhen administered systemically (as opposed, e.g., to topically). Thistoxicity can lead to liver damage (sometimes requiring livertransplantation). Other CYP3A inhibitors, including, e.g., itraconazole,ritonavir, and other CYP3A inhibitors as discussed herein, may havesimilar effects and may require similar warnings.

The simultaneous, or nearly simultaneous (e.g., concomitant) presence oftwo drugs in a subject may alter the effects of one or the other, orboth, drugs. Such alterations are termed drug-drug interactions. Forexample, the required dose of a drug is often strongly affected bytaking the amount and rate of its degradation in, and elimination from,the body (e.g., by liver or kidney action). However, the presence of asecond drug in the body, which is also being acted upon by the liver andkidney, can have significant effects on the amount and rate ofdegradation of the first drug, and can increase the amount of the firstdrug that remains in the body at a given time beyond the amount thatwould have been present at that time in the absence of the second drug.Thus, the presence of a second drug can often increase the effectivedose of the first drug. Where the first drug has toxic side effects,such an increase in effective dose of the first drug may lead todangerous toxicity that would not have been expected were the seconddrug not present.

Concomitant administration of different drugs often leads to adverseeffects since the metabolism and/or excretion of each drug may reduce orinterfere with the metabolism and/or excretion of the other drug(s),thus increasing the effective concentrations of those drugs as comparedto the effective concentrations of those drugs when administered alone.Thus, concomitant administration of drugs is often expected to increasethe risk of toxic effects of one or both of the co-administered drugs.Some drugs, such as ketoconazole, present risk of liver damage(including severe cases including liver failure and even requiring livertransplants) and other toxic effects when administered alone; the riskof such toxic effects is believed to be increased when other drugs areconcomitantly administered. Where a drug, such as ketoconazole, is knownto present a high risk of toxic effects, clinicians will typically avoidits concomitant administration with other drugs.

However, patients often require treatment with multiple drugs, so thatthe potential toxicity of drugs such as ketoconazole presentdisadvantages that can have deleterious consequences for the patient whorequires ketoconazole treatment, or may require foregoing the use ofketoconazole or of some other drug which may have otherwise beenrequired for successful treatment.

Accordingly, improved methods of treatment allowing the administrationof other drugs along with CYP3A inhibitors (such as, e.g., ketoconazole)and along with steroidogenesis inhibitors (such as, e.g., ketoconazole)are desired.

SUMMARY

Applicant discloses herein that CYP3A inhibitors such as, e.g.,ketoconazole, may be concomitantly administered with glucocorticoidreceptor modulators (GRMs) such as the GR antagonist (GRA) mifepristone.Such concomitant administration of a CYP3A inhibitor such asketoconazole and a GRM such as mifepristone is believed to be safe forthe subject, and to provide the therapeutic benefits of both drugs tothe subject, and may allow the reduction in the amount of a GRM, or of aCYP3A inhibitor, administered to the subject; such reduction may reducethe risk of toxic effects of the CYP3A inhibitor concomitantlyadministered with the GRM. In embodiments, the CYP3A inhibitor is astrong CYP3A inhibitor. Such concomitant administration of a CYP3Ainhibitor such as ketoconazole and a GRM such as mifepristone isbelieved to be safe for the subject, and to provide the therapeuticbenefits of both drugs to the subject, may allow the reduction in theamount of GRM administered to the subject, and may allow the reductionin the amount of a CYP3A inhibitor administered to the subject; suchreductions may improve treatment of the patient and may reduce the riskof toxic effects of the CYP3A inhibitor.

Applicant discloses herein that steroidogenesis inhibitors may beconcomitantly administered with glucocorticoid receptor modulators(GRMs) such as the GR antagonist (GRA) mifepristone. Such concomitantadministration of a steroidogenesis inhibitor and a GRM such asmifepristone is believed to be safe for the subject, and to provide thetherapeutic benefits of both drugs to the subject, and may allowconcomitant administration of a GRA and a steroidogenesis inhibitor, mayallow the reduction of the amount of GRM administered to the subject, ormay allow the reduction in the amount of a steroidogenesis inhibitoradministered to the subject; such reductions may reduce the risk oftoxic effects of the steroidogenesis inhibitor. Such concomitantadministration of a steroidogenesis inhibitor and a GRM such asmifepristone is believed to be safe for the subject, and to provide thetherapeutic benefits of both drugs to the subject, and may allow thereduction in the amount of GRM or of a steroidogenesis inhibitoradministered to the subject; such reduction may improve treatment of thesubject and may reduce the risk of toxic effects of the steroidogenesisinhibitor.

For example, Applicant has surprisingly discovered that mifepristone maybe administered to patients concomitantly receiving ketoconazole. Forexample ketoconazole may be administered to patients previously, orconcomitantly, also receiving mifepristone so that the patientconcomitantly receives ketoconazole and mifepristone. Such concomitantadministration of ketoconazole and mifepristone is typically safe forthe patient, provides the therapeutic benefits of both drugs to thepatient, and may allow the reduction in the amount of mifepristoneadministered to the subject; such reduction may provide an effectivedose of mifepristone that is a lower dose, yet still provides similarplasma mifepristone levels as, and may be as effective as, the dose ofmifepristone administered in the absence of ketoconazole. Suchconcomitant administration of ketoconazole and mifepristone provides thetherapeutic benefits of both drugs to the patient, may allow a reductionin the amount of mifepristone administered to the patient, and may allowthe reduction in the amount of ketoconazole administered to the patient;such reduction may reduce the risk of toxic effects of ketoconazole, andmay improve the treatment of the patient.

Applicant's surprising discovery is believed to apply to patientssuffering from a disease or disorder and receiving a CYP3A inhibitor,including a strong CYP3A inhibitor such as ketoconazole; such patientssuffering from a disease or disorder may be safely administered a GRM,such as mifepristone, concomitantly with the administration of a CYP3Ainhibitor such as ketoconazole. Such concomitant administration isbelieved to be safe for the patient. For example, concomitantadministration of ketoconazole and mifepristone surprisingly does notincrease the risk of ketoconazole toxicity in the patient, and isbelieved to be safe for the patient. In particular, Applicant disclosesherein that Cushing's syndrome patients receiving ketoconazole may besafely administered mifepristone concomitantly with the administrationof ketoconazole. Such concomitant administration of ketoconazole andmifepristone to a patient suffering from Cushing's syndrome is believedto be safe for the patient suffering from Cushing's syndrome, which ischaracterized by hypercortisolism. Patients suffering from Cushing'ssyndrome, such as those suffering from endogenous Cushing's syndrome,may suffer hyperglycemia secondary to hypercortisolism. Concomitantadministration of a GRA (such as, e.g., mifepristone) and a CYP3Ainhibitor (such as, e.g., ketoconazole) as disclosed herein is believedto be safe, and to be suitable for controlling hyperglycemia secondaryto hypercortisolism in a patient with endogenous Cushing's syndrome.

In embodiments, a method of treating a patient with Cushing's syndrome,the patient currently taking a GRA at an original dosage, comprisesreducing the amount of GRA from said original dosage to an adjusteddosage that is less than the original dosage when the patient isreceiving concomitant administration of a CYP3A inhibitor. Inembodiments, a method of controlling hyperglycemia secondary tohypercortisolism in a patient with endogenous Cushing's syndrome, thepatient currently taking a GRA at an original dosage, comprises reducingthe amount of GRA from said original dosage to an adjusted dosage thatis less than the original dosage when the patient is receivingconcomitant administration of a CYP3A inhibitor. In embodiments of suchmethods, the adjusted dosage is less than the original dosage by atleast an amount selected from about 5%, 10%, 15%, 20%, 25%, 30%,33^(1/3)%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 66^(2/3)%, 70%, 75%, 80%,85%, and 90% of the original dosage. In embodiments, the adjusted dosageis less than the original dosage by at least 10% of the original dosage.In embodiments, the adjusted dosage is less than the original dosage byat least 25% of the original dosage. In embodiments, the adjusted dosageis less than the original dosage by at least 33^(1/3)% of the originaldosage. In embodiments, the adjusted dosage is less than the originaldosage by at least 50% of the original dosage.

In embodiments, where a GRM such as mifepristone would be prescribed ata first GRM dose, the amount of the GRM (such as mifepristone)administered, when co-administered with a steroidogenesis inhibitor orCYP3A inhibitor such as ketoconazole, may be reduced to a reduced GRMdose that has a smaller amount of GRM as compared to the first GRM doseyet provide effective treatment at the reduced GRM dose co-administeredwith a steroidogenesis inhibitor such as ketoconazole. In embodiments,the clinical status of a subject receiving a reduced GRM doseconcomitantly with a steroidogenesis inhibitor may be monitored forclinical response, e.g., for clinical response to the GRM (such asmifepristone). Monitoring for clinical response may include monitoringfor clinical effect of the GRM, including clinical efficacy of the GRM;for clinical effect of a steroidogenesis inhibitor of CYP3A inhibitor;for possible adverse reaction to a steroidogenesis inhibitor or CYP3Ainhibitor, or the use of a steroidogenesis inhibitor or CYP3A inhibitorin combination with the GRM; for possible side-effects of asteroidogenesis inhibitor or CYP3A inhibitor; for possible side-effectsof the use of a steroidogenesis inhibitor or CYP3A inhibitor incombination with the GRM; or combinations thereof.

In embodiments, the reduced GRM dose may be increased as necessary andas safe for the patient according to such monitoring of the patient. Inembodiments, the reduced GRM dose may be titrated upwards as necessaryand as safe for the subject according to such monitoring of the patientin order to achieve effective treatment of Cushing's syndrome whileremaining safe for the patient with regard to possible adverse effectsof the concomitant administration of the GRM and the CYP3A inhibitor, orof the concomitant administration of the GRM and the steroidogenesisinhibitor.

In embodiments, where a GRM such as mifepristone would be prescribed ata first GRM dose, the amount of the GRM (such as mifepristone)administered, when co-administered with a CYP3A inhibitor, including astrong CYP3A inhibitor such as ketoconazole, may be reduced to a reducedGRM dose that has a smaller amount of GRM as compared to the first GRMdose yet provide effective treatment at the reduced GRM doseco-administered with a CYP3A inhibitor such as ketoconazole. Inembodiments, the clinical status of a patient receiving a reduced GRMdose concomitantly with a CYP3A inhibitor may be monitored, e.g., forclinical effect of the GRM, for clinical effect of the CYP3A inhibitor,for possible adverse reaction to the CYP3A inhibitor or its use incombination with the GRM, for possible side-effects of the CYP3Ainhibitor or its use in combination with the GRM, or combinationsthereof. In embodiments, the reduced GRM dose may be increased asnecessary and as safe for the patient according to such monitoring ofthe patient. In embodiments, the reduced GRM dose may be titratedupwards as necessary and as safe for the patient according to suchmonitoring of the patient in order to achieve effective treatment ofCushing's syndrome while remaining safe for the patient with regard topossible adverse effects of the concomitant administration of the GRMand the CYP3A inhibitor.

Accordingly, Applicant discloses herein that a steroidogenesis inhibitormay be administered to patients concomitantly receiving administrationof a GRM. Accordingly, Applicant discloses herein that a CYP3A inhibitormay be administered to patients concomitantly receiving administrationof a GRM. For example, Applicant discloses herein that ketoconazole, asteroidogenesis inhibitor and a CYP3A inhibitor, may be administered topatients suffering from a disease or disorder, such as, e.g., Cushing'ssyndrome, who are concomitantly receiving administration of a GRM suchas mifepristone. Such concomitant administration of both a GRA (such asmifepristone) and a CYP3A inhibitor (such as ketoconazole) may beadministered to a patient suffering from endogenous Cushing's syndrometo control hyperglycemia secondary to hypercortisolism in the patient.

Accordingly, Applicant discloses herein that GRMs may be administered tosubjects previously, or concomitantly, also receiving administration ofa steroidogenesis inhibitor or a CYP3A inhibitor. For example, Applicantdiscloses herein that GRMs may be administered to subjects sufferingfrom a disease or disorder, such as, e.g., Cushing's syndrome, whopreviously, or are concomitantly, also receiving administration of asteroidogenesis inhibitor or a CYP3A inhibitor such as ketoconazole.Applicant discloses methods for concomitant administration of a GRM anda steroidogenesis or CYP3A inhibitor such as ketoconazole useful fortreating a subject in need of such administration. Subjects in need ofsuch administration include subjects suffering from a disease ordisorder, and include subjects suffering from Cushing's syndrome.Applicant further discloses that such administration of a GRM and asteroidogenesis or a CYP3A inhibitor such as ketoconazole is typicallysafe for the subject, and provides the therapeutic benefits of bothdrugs to the subject. In embodiments, such concomitant administration ofa steroidogenesis or a CYP3A inhibitor such as ketoconazole and a GRMmay allow the reduction in the amount of GRM, or of a steroidogenesis ora CYP3A inhibitor such as ketoconazole, that is administered to thesubject; such reductions may reduce the risk of toxic effects of asteroidogenesis or a CYP3A inhibitor such as ketoconazole, such as,e.g., reduce the risk of liver damage to the subject. The GRM may be,e.g., mifepristone.

Applicant has surprisingly discovered that a steroidogenesis or a CYP3Ainhibitor such as ketoconazole may be concomitantly administered withGRMs, such as GRAs, so that concomitant administration of asteroidogenesis or a CYP3A inhibitor such as ketoconazole and a GRA forexample may provide safe and effective treatment of a patient in need oftreatment. A patient receiving concomitant administration of asteroidogenesis or a CYP3A inhibitor such as ketoconazole and a GRA maybe, for example, a patient in need of treatment for Cushing's syndrome(including Cushing's Disease), breast cancer, prostate cancer, ovariancancer, or other hormone-sensitive cancer. In embodiments, such apatient in need of treatment may receive concomitant administration of asteroidogenesis or a CYP3A inhibitor such as ketoconazole and a GRA,such as mifepristone. In embodiments, such a patient in need oftreatment may receive concomitant administration of ketoconazole andmifepristone.

The methods, compositions, and kits disclosed herein are suitable foruse in treating patients suffering from Cushing's syndrome (includingCushing's Disease); or from prostate cancer and other androgen-sensitivecancers; or from breast cancer, ovarian cancer, or otherhormone-sensitive cancer (e.g., cancer sensitive to estrogen orprogesterone); and are suitable for use in treating subjects sufferingfrom other diseases, disorders, or syndromes.

In embodiments of the methods disclosed herein, a patient currentlyreceiving a GRM, such as mifepristone, is also concomitantlyadministered a steroidogenesis or a CYP3A inhibitor such asketoconazole. In embodiments of the methods disclosed herein, a patientcurrently receiving a GRM, such as mifepristone, as treatment for acondition characterized by excess steroid levels, or as treatment of acondition that is treated by reducing steroid levels or by reducingsteroid effects, is also concomitantly administered a steroidogenesis ora CYP3A inhibitor such as ketoconazole, whereby the patient is treatedfor that condition. In embodiments, the condition is characterized byexcessive cortisol levels. In embodiments, the condition ishyperglycemia secondary to hypercortisolism, e.g., in a patientsuffering from endogenous Cushing's syndrome. In embodiments, thecondition is cancer, and may be a hormone-sensitive cancer. Inembodiments, the hormone sensitive cancer is prostate cancer, breastcancer, or ovarian cancer.

In embodiments of the methods disclosed herein, a patient currentlyreceiving a steroidogenesis or a CYP3A inhibitor such as ketoconazole isalso concomitantly administered a GRM. In embodiments of the methodsdisclosed herein, a patient currently receiving a steroidogenesis or aCYP3A inhibitor such as ketoconazole as treatment for a conditioncharacterized by excess steroid levels, or as treatment of a conditionthat is treated by reducing steroid levels or by reducing steroideffects, is also concomitantly administered a GRM, whereby the patientis treated for that condition. In embodiments, the condition ischaracterized by excessive cortisol levels. In embodiments, thecondition is hyperglycemia secondary to hypercortisolism, e.g., in apatient suffering from endogenous Cushing's syndrome. In embodiments,the condition is hyperglycemia secondary to hypercortisolism, e.g., in apatient suffering from endogenous Cushing's syndrome. In embodiments,the condition is cancer, and may be a hormone-sensitive cancer. Inembodiments, the hormone sensitive cancer is prostate cancer, breastcancer, or ovarian cancer.

Thus, in embodiments of the methods disclosed herein, a patient in needof treatment for a condition is concomitantly administered both a GRM(such as mifepristone) and a steroidogenesis or a CYP3A inhibitor (suchas ketoconazole), whereby the patient is treated for that condition. Inembodiments, the condition is characterized by excessive cortisollevels. In embodiments, the condition is hyperglycemia secondary tohypercortisolism, e.g., in a patient suffering from endogenous Cushing'ssyndrome. In embodiments, the condition is cancer, and may be ahormone-sensitive cancer. In embodiments, the hormone sensitive canceris prostate cancer, breast cancer, or ovarian cancer.

In embodiments, the amount of GRM administered concomitantly with asteroidogenesis or a CYP3A inhibitor is the same amount, orsubstantially the same amount, of GRM previously administered to thepatient prior to concomitant administration of a GRM and asteroidogenesis or a CYP3A inhibitor. In embodiments, the amount of GRIMadministered concomitantly with a steroidogenesis or a CYP3A inhibitoris less than the amount of GRM previously administered to the subjectprior to concomitant administration of a GRM and a steroidogenesis or aCYP3A inhibitor. In embodiments, administration of a reduced amount ofGRM administered concomitantly with a steroidogenesis or a CYP3Ainhibitor is an effective amount of GRM; in embodiments, the reducedamount of GRM administered concomitantly with a steroidogenesis or aCYP3A inhibitor is as effective as the amount of GRM previouslyadministered to the subject prior to concomitant administration of a GRMand a steroidogenesis or a CYP3A inhibitor. The GRM may be mifepristone.The steroidogenesis or a CYP3A inhibitor may be ketoconazole.

In embodiments, the amount of steroidogenesis or a CYP3A inhibitoradministered concomitantly with the GRM is the same amount, orsubstantially the same amount, of steroidogenesis or CYP3A inhibitorpreviously administered to the subject prior to concomitantadministration of a GRM and a steroidogenesis or a CYP3A inhibitor. Inembodiments, the amount of steroidogenesis or CYP3A inhibitoradministered concomitantly with the GRM is less than the amount ofsteroidogenesis or CYP3A inhibitor previously administered to thesubject prior to concomitant administration of a GRM and asteroidogenesis or a CYP3A inhibitor. In embodiments, administration ofa reduced amount of steroidogenesis or CYP3A inhibitor administeredconcomitantly with a GRM is an effective amount of steroidogenesis orCYP3A inhibitor; in embodiments, the reduced amount of steroidogenesisor CYP3A inhibitor administered concomitantly with a GRM is as effectiveas the amount of steroidogenesis or CYP3A inhibitor previouslyadministered to the subject prior to concomitant administration of a GRMand a steroidogenesis or a CYP3A inhibitor. The GRM may be mifepristone.The steroidogenesis or CYP3A inhibitor may be ketoconazole.

Concomitant administration of a GRM and steroidogenesis or a CYP3Ainhibitor may be administration of a GRM followed within a short time byadministration of a steroidogenesis or a CYP3A inhibitor. Inembodiments, concomitant administration of a GRM and a steroidogenesisor a CYP3A inhibitor may be administration of mifepristone followedwithin a short time by administration of ketoconazole. Concomitantadministration of a GRM and a steroidogenesis or a CYP3A inhibitor maybe administration of a steroidogenesis or a CYP3A inhibitor followedwithin a short time by administration of a GRM. In embodiments,concomitant administration of a GRM and a steroidogenesis or a CYP3Ainhibitor may be administration of ketoconazole followed within a shorttime by administration of mifepristone. Concomitant administration of aGRM and a steroidogenesis or a CYP3A inhibitor may be simultaneousadministration of a GRM and a steroidogenesis or a CYP3A inhibitor. Inembodiments, concomitant administration of a GRM and a steroidogenesisor a CYP3A inhibitor may be simultaneous administration of mifepristoneand ketoconazole.

In embodiments, the GRM is a steroidal GRM, such as, e.g., mifepristone.In embodiments, the GRM is a non-steroidal GRM. In embodiments, the GRMis a glucocorticoid receptor antagonist (GRA). In embodiments, the GRAis a steroidal GRA. In embodiments, the GRA is mifepristone. Inembodiments, the GRA is a non-steroidal GRA. In embodiments, the GRA isa non-steroidal GRA selected from a GRA having a cyclohexyl-pyrimidinebackbone, GRA having a fused azadecalin backbone, a GRA having aheteroaryl ketone fused azadecalin backbone, and a GRA having anoctahydro fused azadecalin backbone.

In embodiments, a patient is concomitantly administered a GRM andketoconazole; in embodiments, the GRM is mifepristone. In embodiments,concomitant administration comprises simultaneous administration of aGRM and ketoconazole to a patient, where the GRM is mifepristone. Inembodiments, the amount of ketoconazole administered concomitantly withthe mifepristone is the same amount, or substantially the same amount,of ketoconazole previously administered to the subject prior toconcomitant administration of mifepristone and ketoconazole. Inembodiments, the amount of ketoconazole administered concomitantly withthe mifepristone is less than the amount of ketoconazole previouslyadministered to the subject prior to concomitant administration ofmifepristone and ketoconazole.

Accordingly, in embodiments, Applicant discloses herein a method fortreating a patient who is suffering from Cushing's syndrome or acondition associated with Cushing's syndrome, said patient receiving afirst dose of a glucocorticoid receptor antagonist (GRA), said methodcomprising: concomitantly administering to the patient a dose of a CYP3Ainhibitor and a reduced dose of said GRA, wherein said reduced GRA doseconsists of a GRA dose that is less than the first GRA dose, whereby thepatient is treated for Cushing's syndrome or a condition associated withCushing's syndrome by concomitant administration of said CYP3A inhibitorand a reduced dose said GRA. Conditions associated with Cushing'ssyndrome include, without limitation, hyperglycemia secondary tohypercortisolism, e.g., hyperglycemia secondary to hypercortisolism in apatient suffering from endogenous Cushing’ syndrome. Conditionsassociated with Cushing's syndrome also include, without limitation,hyperglycemia secondary to hypercortisolism in an adult Cushing'ssyndrome patient who has type 2 diabetes mellitus or glucoseintolerance. Conditions associated with Cushing's syndrome furtherinclude, without limitation, hyperglycemia secondary to hypercortisolismin an adult Cushing's syndrome patient who has a) type 2 diabetesmellitus or glucose intolerance, and b) has failed surgery or is not acandidate for surgery.

In embodiments, the dosage of said reduced GRA dose is less than thedosage of said first GRA dose by at least an amount selected from about5%, 10%, 15%, 20%, 25%, 30%, 33^(1/3)%, 35%, 40%, 45%, 50%, 55%, 60%,65%, 66^(2/3)%, 70%, 75%, 80%, 85%, and 90% of the first GRA dose. Inembodiments, the dosage of said reduced GRA dose is less than the dosageof said first GRA dose by about 300 milligrams (mg) of said GRA. Inembodiments, the dosage amount of said first GRA dose is 600 mg orhigher of said GRA. In embodiments, said reduced GRA dose is a GRA doseselected from the group of GRA doses consisting of about 1500 milligrams(mg) GRA, about 1200 mg GRA, about 900 mg GRA, and about 600 mg GRA. Inembodiments, said reduced GRA dose is 900 mg of the GRA. In embodiments,said reduced GRA dose is 600 mg of the GRA. In embodiments, the reducedGRA dose is a daily GRA dose. In embodiments, the methods furthercomprise titrating upwards the dosage of the reduced GRA dose. Inembodiments, such titrating upwards comprises increasing the dosage ofthe reduced GRA dose in increments of 300 milligrams (mg) of GRA. Inembodiments, the interval of time between upward titration of a reduceddose, or of an upwardly titrated reduced dose, and a subsequent upwardtitration of a dosage of the reduced dose of mifepristone is selectedfrom one week, two weeks, three weeks, and four weeks. In embodiments,the methods include monitoring the patient for clinical response to theGRA. In embodiments, such titrating upwards follows a determination thatsaid reduced GRA dose is associated with a decrease in clinical responseto the GRA. In embodiments, monitoring the patient for clinical responseto the GRA comprises monitoring the patient for glucose control,anti-diabetic medication requirement, insulin level, psychiatricsymptoms, cushingoid appearance, acne, hirsutism, body weight, orcombinations thereof. In embodiments, such titrating upwards is cappedat a dosage level of 900 milligrams per day. In embodiments, suchtitrating upwards is capped at a dosage level of 600 milligrams per day.In embodiments of the methods disclosed herein, the reduced GRA dose isa daily dose of 900 mg mifepristone. In embodiments of the methodsdisclosed herein, the reduced GRA dose is a daily dose of 600 mgmifepristone.

Embodiments of the methods disclosed herein are directed to treating apatient suffering from Cushing's syndrome or a condition associated withCushing's syndrome. In embodiments, the patient suffering from Cushing'ssyndrome or a condition associated with Cushing's syndrome is a patientsuffering from a condition associated with endogenous Cushing'ssyndrome. In embodiments, treating a patient who is suffering fromCushing's syndrome or a condition associated with Cushing's syndromecomprises treating a patient who is suffering from hyperglycemiasecondary to hypercortisolism. In embodiments, treating patient who issuffering from Cushing's syndrome or a condition associated withCushing's syndrome comprises treating hyperglycemia secondary tohypercortisolism in a Cushing's syndrome patient having type 2 diabetesmellitus or glucose intolerance. In embodiments, treating a patient whois suffering from Cushing's syndrome or a condition associated withCushing's syndrome comprises treating hyperglycemia secondary tohypercortisolism in a Cushing's syndrome patient, said patient a) havingtype 2 diabetes mellitus or glucose intolerance, and b) having failedsurgery or is not a candidate for surgery. In embodiments, treating apatient who is suffering from Cushing's syndrome or a conditionassociated with Cushing's syndrome comprises administering mifepristoneto control hyperglycemia secondary to hypercortisolism in an adultCushing's syndrome patient who has a) type 2 diabetes mellitus orglucose intolerance, and b) has failed surgery or is not a candidate forsurgery.

In embodiments, Applicant discloses herein a method for treating apatient who is suffering from Cushing's syndrome or a conditionassociated with Cushing's syndrome, said patient receiving a first doseof a glucocorticoid receptor antagonist (GRA), said method comprising:concomitantly administering to the patient a dose of said CYP3Ainhibitor and a first dose of a glucocorticoid receptor antagonist(GRA), whereby the patient is treated for Cushing's syndrome or acondition associated with Cushing's syndrome by concomitantadministration of said CYP3A inhibitor and said GRA. In embodiments, thefirst GRA dose is selected from a GRA dose no greater than 900milligrams (mg) per day of the GRA, and no greater than 600 mg per dayof the GRA. In embodiments, the patient had been administered a dose ofthe CYP3A inhibitor prior to said administering of said first GRA dose.In embodiments, said concomitant administration of the CYP3A inhibitorand said GRA comprises administration of said first GRA dose to apatient having detectable levels of said CYP3A inhibitor, wherein saidpatient had been administered a dose of the CYP3A inhibitor prior tosaid administration of said first GRA dose. In embodiments, methodsfurther comprise titrating upwards the dosage of a subsequent GRA dose,wherein the dosage of said subsequent GRA dose is a greater amount ofGRA than the amount of GRA of the first GRA dose. In embodiments, suchtitrating upwards comprises increasing the dosage of the subsequent GRAdose in increments of 300 milligrams (mg) of GRA. In embodiments, theinterval of time between upward titration of a subsequent GRA dose, orof an upwardly titrated subsequent GRA dose, and a subsequent upwardtitration of the dosage of the subsequent GRA dose is selected from oneweek, two weeks, three weeks, and four weeks.

In embodiments of the methods disclosed herein, the CYP3A inhibitor is astrong CYP3A inhibitor selected from the group consisting ofketoconazole, itraconazole, nefazodone, ritonavir, nelfinavir,indinavir, atazanavir, amprenavir and fosamprenavir, clarithromycin,conivaptan, lopinavir/ritonavir, posaconazole, saquinavir,telithromycin, and voriconazole. In embodiments, the CYP3A inhibitor isketoconazole.

In embodiments of the methods disclosed herein, the GRA is mifepristone.

The methods disclosed herein provide advantages including expandedtreatment options for patients suffering from conditions includingCushing's syndrome, Cushing's Disease, prostate cancer, breast cancer,ovarian cancer, and other conditions.

The methods disclosed herein provide advantages including improvedtreatments for patients suffering from conditions including Cushing'ssyndrome, Cushing's Disease, prostate cancer, breast cancer, ovariancancer, and other conditions, where such improved treatments may includethe ability to alter the amount of a GRM, such mifepristone,administered to the patient by administering a GRM such as mifepristoneconcomitantly with ketoconazole. In embodiments, such improvedtreatments include the ability to reduce the amount of a GRM, such asmifepristone, administered to a subject.

The methods disclosed herein provide advantages including improvedtreatments for patients suffering from conditions including Cushing'ssyndrome, Cushing's Disease, prostate cancer, breast cancer, ovariancancer, and other conditions, where such improved treatments may includethe ability to alter the amount of ketoconazole administered to thepatient by administering a GRM such as mifepristone concomitantly withketoconazole. In embodiments, such improved treatments include theability to reduce the amount of ketoconazole administered to a subjectand thus to reduce risk of toxic effects of the ketoconazole.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the mean and standard deviation of mifepristone and itsmetabolites RU42633, RU42698, and RU42848 measured in healthy malevolunteers prior to administration of mifepristone on days one throughseventeen. Ketoconazole was also administered on daysthirteen-seventeen.

FIG. 2 shows the plasma concentration profile of mifepristone measuredin healthy male volunteers on day twelve (before administration ofketoconazole) and on day seventeen (the fifth day of ketoconazoleadministration).

DETAILED DESCRIPTION

Ketoconazole strongly inhibits corticosteroid synthesis; thus,ketoconazole strongly reduces cortisol levels in subjects administeredketoconazole. However, there is concern over its use, for example, dueto potential hepatoxicity (see, e.g., Castinetti et al., J ClinEndocrinol Metab 99(5):1623-1630 (2014)).

According to the U.S. Food and Drug Administration (FDA) definition,strong CYP3A inhibitors are expected to increase the AUC of other drugsby greater than five-fold. Ketoconazole is identified by the FDA as astrong CYP3A inhibitor (See FDA web posting: Drug Development and DrugInteractions: Table of Substrates, Inhibitors and Inducers).

Surprisingly, as disclosed herein, concomitant administration ofmifepristone and ketoconazole causes only a small increase in the plasmalevels of mifepristone, and does not cause the large increases thatwould have been expected for such concomitant administration.

Applicant has surprisingly found that concomitant administration ofmifepristone and ketoconazole causes only a small increase in the AUCand in the Cmax of mifepristone in subjects receiving mifepristone alonefor twelve days, and then administered both mifepristone andketoconazole concomitantly. The Cmax of mifepristone administeredconcomitantly with ketoconazole is increased by less than two-fold (amere 28% increase in mifepristone Cmax) and the AUC of mifepristoneadministered concomitantly with ketoconazole is increased by less thantwo-fold (a mere 38% increase in mifepristone AUC) in subjects receiving600 mg mifepristone per day who then are given 400 mg ketoconazole (200mg twice per day)).

Also surprisingly, as disclosed herein, concomitant administration ofketoconazole and mifepristone also caused smaller increases inketoconazole levels than would be expected. The Cmax of ketoconazoleadministered concomitantly with mifepristone is increased by less thanfour-fold (365% increase in ketoconazole Cmax) and the AUC ofketoconazole administered concomitantly with mifepristone is increasedby less than three-fold (253% increase in ketoconazole AUC) whencomparing ketoconazole levels on the first day of concomitantadministration of both drugs as compared to the ketoconazole levels insubjects on the fifth day of receiving 400 mg ketoconazole (200 mg twiceper day) concomitantly with 600 mg mifepristone per day.

Ketoconazole is a strong inhibitor of steroidogenesis; thus it isbelieved that ketoconazole may serve as an examplar for other stronginhibitors of steroidogenesis and that these results indicate thatmifepristone, and other glucocorticoid receptor modulators, includingother glucocorticoid receptor antagonists, may be safely administeredconcomitantly with steroidogenesis inhibitors according to the methodsdisclosed herein.

Ketoconazole is a strong inhibitor of CYP3A enzymes; thus it is believedthat ketoconazole may serve as an examplar for other strong inhibitorsof CYP3A enzymes and that these results indicate that mifepristone, andother glucocorticoid receptor modulators, including other glucocorticoidreceptor antagonists, may be safely administered concomitantly withCYP3A enzyme inhibitors according to the methods disclosed herein.

Applicant discloses herein methods for the safe concomitantadministration of both a glucocorticoid receptor modulator (GRM) andsteroidogenesis inhibitor to a subject. Applicant discloses herein thesurprising finding that both a GRM such as mifepristone and asteroidogenesis inhibitor such as ketoconazole may be safelyadministered to a subject at the same, or nearly the same, time (i.e.,the GRM and the steroidogenesis inhibitor may be concomitantlyadministered).

Applicant discloses herein methods for the safe concomitantadministration of both a glucocorticoid receptor modulator (GRM) andCYP3A inhibitor to a subject. Applicant discloses herein the surprisingfinding that both a GRM such as mifepristone and a CYP3A inhibitor suchas ketoconazole may be safely administered to a subject at the same, ornearly the same, time (i.e., the GRM and the CYP3A may be concomitantlyadministered).

Applicant discloses herein the surprising finding that a subjectreceiving ketoconazole, which is a steroidogenesis inhibitor and is aCYP3A inhibitor, may also be safely administered an effective dose ofmifepristone, which is a glucocorticoid receptor modulator (GRM), e.g.,a glucocorticoid receptor antagonist (GRA). Applicant also disclosesherein the surprising finding that a subject receiving mifepristone,which is a glucocorticoid receptor modulator (GRM), e.g., aglucocorticoid receptor antagonist (GRA), may also be safelyadministered ketoconazole, which is a steroidogenesis inhibitor and is aCYP3A inhibitor.

In embodiments of the methods disclosed herein, a subject receiving aGRM (such as, e.g., a glucocorticoid receptor antagonist (GRA) such asmifepristone) may be safely administered an effective dose of asteroidogenesis inhibitor such as ketoconazole. In embodiments of themethods disclosed herein, a subject may be safely administeredketoconazole and a reduced dose of a GRM, where the reduced dose of aGRM is an effective dose of GRM that is a smaller GRM dose than the GRMdose administered in the absence of a steroidogenesis inhibitor such asketoconazole. In embodiments of the methods disclosed herein, a subjectmay be safely administered a GRM and a reduced dose of a steroidogenesisinhibitor such as ketoconazole, where the reduced dose of thesteroidogenesis inhibitor is an effective dose of the steroidogenesisinhibitor that is a smaller dose than the a steroidogenesis inhibitordose administered in the absence of the GRM. In embodiments of themethods disclosed herein, a subject receiving a steroidogenesisinhibitor such as, e.g., ketoconazole, may be safely administered aneffective dose of a GRM, such as, e.g., mifepristone. In embodiments ofthe methods disclosed herein, a subject receiving a GRM, such as, e.g.,mifepristone, may be safely administered an effective dose of asteroidogenesis inhibitor such as, e.g., ketoconazole.

These methods may be applied to subjects suffering from diseases ordisorders as well as other subjects, including subjects suffering fromCushing's syndrome. Such concomitant administration of a steroidogenesisinhibitor such as ketoconazole with a GRM would have been expected toproduce toxic side effects due to, e.g., an adverse effect onsteroidogenesis inhibitor metabolism due to the added GRM (e.g., wherethe steroidogenesis inhibitor is ketoconazole, a previously safeketoconazole dose would have been expected to be a toxic dose in thepresence of added GRM (e.g., mifepristone)).

In particular, Applicant discloses herein that patients suffering from adisease or disorder and receiving ketoconazole may be safelyadministered mifepristone concomitantly with the administration ofketoconazole. Such concomitant administration of ketoconazole andmifepristone surprisingly does not increase the risk of toxicity in thepatient, and is believed to be safe for the patient. In particular,Applicant discloses herein that Cushing's syndrome patients receivingketoconazole may be safely administered mifepristone concomitantly withthe administration of ketoconazole. Such concomitant administration ofketoconazole and mifepristone surprisingly does not increase the risk oftoxicity in humans, and is believed to be safe for a patient sufferingfrom Cushing's syndrome.

Thus, Applicant discloses herein surprising and useful methods forconcomitant administration of a steroidogenesis inhibitor such as, e.g.,ketoconazole, and a GRM such as, e.g., mifepristone, which provide thebenefits of improved treatment without substantially increased risk ofadverse treatment side-effects. For example, Applicant provides hereinsurprising and useful methods for concomitant administration ofketoconazole and mifepristone, which provide the benefits of both drugswithout substantially increased risk of ketoconazole toxicity, which canhave serious adverse effects on the liver.

Thus, contrary to the expectation that the presence of a GRM such asmifepristone along with a steroidogenesis inhibitor (e.g., ketoconazole)in a patient would increase the toxicity of the steroidogenesisinhibitor beyond that expected for such a dose of steroidogenesisinhibitor alone, Applicant has discovered that administering a) both aGRM (e.g., mifepristone) and a steroidogenesis inhibitor (e.g.,ketoconazole) to a subject, or b) administering a GRM (e.g.,mifepristone) to a subject who has recently been given a steroidogenesisinhibitor (e.g., ketoconazole), or c) administering a steroidogenesisinhibitor (e.g., ketoconazole) soon after GRM (e.g., mifepristone)administration to a subject, concomitant administration of a GRM and asteroidogenesis inhibitor does not increase the expected toxicity of thesteroidogenesis inhibitor. In embodiments, concomitant administration ofa steroidogenesis inhibitor and a GRM allows for administration of aneffective dose of GRM that is a reduced GRM dose as compared to the GRMdose administered in the absence of the steroidogenesis inhibitor.

In embodiments, concomitant administration of ketoconazole andmifepristone allows for administration of an effective dose ofmifepristone that is a reduced dose of mifepristone as compared to themifepristone dose administered in the absence of ketoconazole. Forexample, Applicant has discovered that concomitant administration ofmifepristone and ketoconazole makes it possible to reduce the dose ofmifepristone while maintaining sufficient mifepristone levels foreffective therapy for the patient. Such a reduction in mifepristone doseprovides the benefit of reducing the amount of mifepristone administeredto the subject. Embodiments in which a subject is concomitantlyadministered ketoconazole and mifepristone allow for mifepristone dosereduction (as compared to the mifepristone dose in the absence ofketoconazole) include, e.g., Cushing's syndrome and hormone-sensitivecancers such as breast, ovarian, and prostate cancer, and otherdisorders susceptible of treatment by mifepristone.

In embodiments, the reduced dose of mifepristone administered to asubject also concomitantly receiving ketoconazole is a dose ofmifepristone that is at least about 5% less than the original dose ofmifepristone, where the original dose of mifepristone is the dose thesubject had been, or would have been, administered in the absence ofketoconazole co-administration. In embodiments, the reduced dose ofmifepristone is a dose of mifepristone that is at least about 10% lessthan the original dose of mifepristone; and may be a dose ofmifepristone that is at least about 15%, or about 20%, or about 22%, orabout 23%, or about 25%, or about 28%, or about 29%, or about 33%, orabout 38%, or about 40%, or about 50%, or about 66%, or about 75% lessthan the original dose of mifepristone.

In embodiments, the reduced dose of mifepristone administered to asubject also concomitantly receiving ketoconazole is a dose ofmifepristone that is 300 mg less mifepristone than the amount of theoriginal dose of mifepristone. In embodiments, the reduced dose ofmifepristone administered to a subject also concomitantly receivingketoconazole is a dose of mifepristone that is an amount of mifepristonethat is an integer multiple of 300 mg mifepristone less than the amountof the original dose of mifepristone. In embodiments, the integer of theinteger multiple is selected from the integers 1, 2, 3, 4, and 5.

In embodiments, the reduced dose of mifeprikone administered to asubject also concomitantly receiving ketoconazole is a dose ofmifepristone that is about 900 mg mifepristone; or is about 600 mgmifepristone; or is about 300 mg mifepristone. In embodiments, thereduced dose of mifepristone administered to a subject alsoconcomitantly receiving ketoconazole is a dose of mifepristone that isabout 300 mg mifepristone administered only every other day; or is about300 mg mifepristone administered every third day; or is about 300 mgmifepristone administered every fourth day. For example, where theoriginal dose of mifepristone is about 1500 mg per day, the reduced doseof mifepristone may be about 1200 mg of mifepristone administered everyday; or may be about 900 mg of mifepristone administered every day; ormay be about 600 mg of mifepristone administered every day; or may beabout 300 mg of mifepristone administered every day. For example, wherethe original dose of mifepristone is about 1200 mg per day, the reduceddose of mifepristone may be about 900 mg of mifepristone administeredevery day; or may be about 600 mg of mifepristone administered everyday; or may be about 300 mg of mifepristone administered every day. Forexample, where the original dose of mifepristone is about 900 mg perday, the reduced dose of mifepristone may be about 600 mg ofmifepristone administered every day; or may be about 300 mg ofmifepristone administered every day; or may be about 300 mg ofmifepristone administered every other day. For example, where theoriginal dose of mifepristone is about 600 mg per day, the reduced doseof mifepristone may be about 300 mg of mifepristone administered everyday; or may be about 300 mg of mifepristone administered every otherday; or may be about 300 mg of mifepristone administered every thirdday. For example, where the original dose of mifepristone is about 300mg per day, the reduced dose of mifepristone may be about 300 mg ofmifepristone administered every other day; or may be about 300 mg ofmifepristone administered every third day; or may be about 300 mg ofmifepristone administered every fourth day.

In embodiments in which a subject has been receiving about 1800 mgmifepristone per day, and concomitant administration of mifepristone andketoconazole is indicated, the reduced dose of mifepristone may be about1500 mg mifepristone per day; may be about 1200 mg mifepristone per day;may be about 900 mg mifepristone per day; may be about 600 mgmifepristone per day; may be about 300 mg mifepristone per day; may beabout 300 mg mifepristone every other day; or may be about 300 mgmifepristone every third day. In embodiments in which a subject has beenreceiving about 1500 mg mifepristone per day, and concomitantadministration of mifepristone and ketoconazole is indicated, thereduced dose of mifepristone may be about 1200 mg mifepristone per day;may be about 900 mg mifepristone per day; may be about 600 mgmifepristone per day; may be about 300 mg mifepristone per day; may beabout 300 mg mifepristone every other day; or may be about 300 mgmifepristone every third day. In embodiments in which a subject has beenreceiving about 1200 mg mifepristone per day, and concomitantadministration of mifepristone and ketoconazole is indicated, thereduced dose of mifepristone may be about 900 mg mifepristone per day;may be about 600 mg mifepristone per day; may be about 300 mgmifepristone per day; may be about 300 mg mifepristone every other day;or may be about 300 mg mifepristone every third day. In embodiments inwhich a subject has been receiving about 900 mg mifepristone per day,and concomitant administration of mifepristone and ketoconazole isindicated, the reduced dose of mifepristone may be about 600 mgmifepristone per day; may be about 300 mg mifepristone per day; may beabout 300 mg mifepristone every other day; or may be about 300 mgmifepristone every third day. In embodiments in which a subject has beenreceiving about 600 mg mifepristone per day, and concomitantadministration of mifepristone and ketoconazole is indicated, thereduced dose of mifepristone may be about 300 mg mifepristone per day;may be about 300 mg mifepristone every other day; may be about 300 mgevery third day; or may be about 300 mg mifepristone every fourth day.In embodiments in which a subject has been receiving about 300 mgmifepristone per day, and concomitant administration of mifepristone andketoconazole is indicated, the reduced dose of mifepristone may be about300 mg mifepristone every other day; may be about 300 mg every thirdday; or may be about 300 mg mifepristone every fourth day.

In embodiments in which a subject has been receiving a first dose ofmifepristone (e.g. a daily dose of mifepristone of about 1800 mg/day, orabout 1500 mg/day, or about 1200 mg/day, or about 900 mg/day, or about600 mg/day, or about 300 mg/day), and concomitant administration ofmifepristone and ketoconazole is indicated, the subject may beadministered a reduced dose of mifepristone, where the amount of thereduced dose is less than the original mifepristone dose by about 300 mgmifepristone per day, and the subject may be monitored for clinicaleffects of the drugs, including monitoring for clinical response tomifepristone. In embodiments in which a subject has been receiving afirst dose of mifepristone (e.g. a daily dose of mifepristone of about1800 mg/day, or about 1500 mg/day, or about 1200 mg/day, or about 900mg/day, or about 600 mg/day, or about 300 mg/day), and concomitantadministration of mifepristone and ketoconazole is indicated, thesubject may be administered a reduced dose of mifepristone, where theamount of the reduced dose is less than the original mifepristone doseby about 300 mg mifepristone per day, and the reduced dose ofmifepristone may be subsequently titrated upwards (i.e., increased insubsequent dose administrations) in increments of about 300 mgmifepristone. In embodiments, such upward titration of the reduced dosein increments of 300 mg/day may be subjected to a maximum daily dosageof about 600 mg/day, or of about 900 mg/day, or of about 1200 mg/day, orof about 1500 mg/day. In embodiments, such upward titration of thedosage of the reduced daily dose of mifepristone administered per day iscapped at a maximum daily dose, wherein said maximum daily dose isselected from the group consisting of 900 milligrams (mg) mifepristoneper day and 600 mg mifepristone per day.

The subject may be monitored for clinical effects of the drugs, e.g.,for clinical response to the GRA (e.g., mifepristone), adverse events,side-effects of any drug, at any stage or at all stages, of suchincremental upward titration of the mifepristone dosage. The interval oftime between administration of a reduced dose, or of an upwardlytitrated reduced dose, and an upward titration of a dose of mifepristonemay be an interval selected from two days, four days, one week, twoweeks, one month, two months, and three months. In embodiments, theinterval of time between upward titration of a reduced dose, or of anupwardly titrated reduced dose, and a subsequent upward titration of adosage of the reduced dose of mifepristone is selected from one week,two weeks, three weeks, and four weeks. Monitoring the patient forclinical response may include monitoring the patient (e.g., to identifyor determine if there are changes in) for glucose control, anti-diabeticmedication requirement, insulin level, psychiatric symptoms, cushingoidappearance, acne, hirsutism, and monitoring the body weight of thepatient (e.g., to identify or determine if there are changes in any oneor more of these symptoms and characteristics).

In embodiments in which a subject has been receiving a first dose ofmifepristone (e.g. a daily dose of mifepristone of about 1800 mg/day, orabout 1500 mg/day, or about 1200 mg/day, or about 900 mg/day, or about600 mg/day, or about 300 mg/day), and concomitant administration ofmifepristone and ketoconazole is indicated, the subject may beadministered a reduced dose of mifepristone, where the amount of thereduced dose is less than the original mifepristone dose, and thereduced dose of mifepristone may be about 1500 mg mifepristone per day,or about 1500 mg/day, or about 1200 mg/day, or about 900 mg/day, orabout 600 mg/day, or about 300 mg/day; and the subject may be monitoredfor clinical response to the GRA, or for other clinical effects of thedrugs. In such embodiments, the reduced dose of mifepristone may besubsequently titrated upwards (i.e., increased in subsequent doseadministrations) in increments of about 300 mg mifepristone. Inembodiments, such upward titration of the reduced dose in increments of300 mg/day may be subjected to a maximum daily dosage of about 600mg/day, or of about 900 mg/day, or of about 1200 mg/day, or of about1500 mg/day. In embodiments, such upward titration of the dosage of thereduced daily dose of mifepristone administered per day is capped at amaximum daily dose, wherein said maximum daily dose is selected from thegroup consisting of 900 milligrams (mg) mifepristone per day and 600 mgmifepristone per day.

The subject may be monitored for clinical response to the drugs,including e.g., clinical response to the GRA. (e.g., mifepristone), foradverse events, side-effects of any of the drugs, at any stage, or atall stages, of such incremental upward titration of the mifepristonedosage. Upward titration of a reduced dose of mifepristone may beperformed every two days, or every four days, or every week, or everytwo weeks, or every month, or every two months. In embodiments, theinterval of time between upward titration of a reduced dose, or of anupwardly titrated reduced dose, and a subsequent upward titration of adosage of the reduced dose of mifepristone is selected from one week,two weeks, three weeks, and four weeks.

Applicant discloses herein that concomitant treatment with bothmifepristone and ketoconazole may lead to small increases in plasmalevels of mifepristone as measured by Cmax and as measured by AUC. Forexample, as disclosed in Table 3 below, concomitant administration ofmifepristone and ketoconazole led to about 28% (27.59%, or about 30%)increase in mifepristone Cmax and about 38% (38.01%, about 40%) increasein mifepristone AUC, Thus, in embodiments, a mifepristone doseadministered to a subject receiving concomitant administration ofmifepristone and ketoconazole may be reduced in compensation for such asmall increase in mifepristone plasma levels. In embodiments in which asubject has been receiving mifepristone, and concomitant administrationof mifepristone and ketoconazole is indicated, the reduced dose ofmifepristone may be reduced by about 22% of the original dose ofmifepristone. In embodiments in which a subject has been receivingmifepristone, and concomitant administration of mifepristone andketoconazole is indicated, the reduced dose of mifepristone may bereduced by about 23% of the original dose of mifepristone. Inembodiments in which a subject has been receiving mifepristone, andconcomitant administration of mifepristone and ketoconazole isindicated, the reduced dose of mifepristone may be reduced by about 28%of the original dose of mifepristone. In embodiments in which a subjecthas been receiving mifepristone, and concomitant administration ofmifepristone and ketoconazole is indicated, the reduced dose ofmifepristone may be reduced by about 29% of the original dose ofmifepristone. In embodiments, the reduced dose of mifepristone is a doseof mifepristone that is at least about 90% of the original dose ofmifepristone; and may be a dose of mifepristone that is at least about85%, or about 80%, or about 78%, or about 77%, or about 75%, or about72%, or about 71%, or about 67%, or about 62%, or about 60%, or about50%, or about 34%, or about 25% of the original dose of mifepristone.

Applicant further discloses herein that, since mifepristone providesadded therapeutic benefit synergistic with that of ketoconazole,concomitant administration of mifepristone and ketoconazole makes itpossible to reduce the dose of ketoconazole while maintainingmifepristone levels effective for therapy for a patient. Such areduction in ketoconazole dose provides the benefit of reducing the riskof toxic side-effects associated with all ketoconazole treatments. Thus,concomitant administration of ketoconazole and mifepristone, by allowingreduced ketoconazole dose, provides improved, synergistic therapeuticbenefits. In embodiments, such ketoconazole dose reduction may be usedto wean the patient off ketoconazole, leading to lower and lowerketoconazole doses, thereby reducing the risk of ketoconazole toxicity.In embodiments, such ketoconazole dose reduction may be used to wean thepatient off ketoconazole, leading to lower and lower ketoconazole doses,with concomitant upward adjustment of mifepristone dosage as needed,ultimately leading to treatment with mifepristone alone and cessation ofketoconazole treatment (lessening the risk of liver damage and othertoxicities). Embodiments in which concomitant administration ofketoconazole and mifepristone may lead to ketoconazole dose reduction(as compared to the ketoconazole dose in the absence of mifepristone)include, e.g., Cushing's syndrome and hormone-sensitive cancers such asbreast, ovarian, and prostate cancer, and other disorders susceptible oftreatment by mifepristone.

In embodiments, concomitant administration of ketoconazole andmifepristone allows for administration of an effective dose ofketoconazole that is a reduced dose of ketoconazole as compared to theketoconazole dose administered in the absence of mifepristone. Forexample, Applicant discloses herein that concomitant administration ofmifepristone and ketoconazole makes it possible to reduce the dose ofketoconazole while maintaining effective therapy for the patient. Such areduction in ketoconazole dose provides the benefit of reducing theamount of ketoconazole administered to the subject. Embodiments in whicha subject is concomitantly administered ketoconazole and mifepristoneallow for ketoconazole dose reduction (as compared to the ketoconazoledose in the absence of mifepristone) include, e.g., Cushing's syndromeand hormone-sensitive cancers such as breast, ovarian, and prostatecancer, and other disorders susceptible of treatment by ketoconazole andother steroidogenesis inhibitors.

In embodiments, the reduced dose of ketoconazole administered to asubject also concomitantly receiving mifepristone is a dose ofketoconazole that is at least about 5% less than the original dose ofketoconazole, where the original dose of ketoconazole is the dose thesubject had been, or would have been, administered in the absence ofmifepristone co-administration. In embodiments, the reduced dose ofketoconazole is a dose of ketoconazole that is at least about 10% lessthan the original dose of ketoconazole; and may be a dose ofketoconazole that is at least about 15%, or about 20%, or about 25%, orabout 33%, or about 50%, or about 66%, or about 75% less than theoriginal dose of ketoconazole.

Applicant provides definitions of some terms used in the presentdisclosure.

Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts.

“Patient”, “patient in need”, “subject”, “subject in need” and the likerefer to a person having, or suspected of having, a disease or conditionwhich may be treated by administration of a therapeutic drug.

As used herein, the term “Cushing's syndrome” refers to an array ofsymptoms caused by excess cortisol. Cushing's syndrome includesendogenous Cushing's syndrome and ectopic Cushing's syndrome. Suchsymptoms include, for example, elevated blood pressure, elevated bloodglucose, increased weight (typically in the mid-section, and in the facecausing a characteristic “moon-face”), immune suppression, thin skin,acne, depression, hirsutism, and other symptoms.

As used herein, “Cushing's Disease” refers to pituitary-dependentCushing's syndrome, e.g., excess cortisol caused by pituitaryabnormality (typically a pituitary tumor). Cushing's Disease is thus adisease that is a particular type of Cushing's syndrome. The termCushing's syndrome thus includes reference to Cushing's Disease.

As used herein, a “patient suffering from Cushing's syndrome” refers toany patient suffering from Cushing's syndrome, including endogenousCushing's syndrome; Cushing's Disease; or a condition associated withCushing's syndrome. A condition associated with Cushing's syndrome maybe, without limitation, a condition associated with endogenous Cushing'ssyndrome; hyperglycemia secondary to hypercortisolism; a condition ofhypercortisolism in an endogenous Cushing's syndrome patient, saidpatient having type 2 diabetes mellitus or glucose intolerance; acondition of hyperglycemia secondary to hypercortisolism in anendogenous Cushing's syndrome patient, said patient having type 2diabetes mellitus or glucose intolerance and having failed surgery;hyperglycemia secondary to hypercortisolism in an endogenous Cushing'ssyndrome patient, said patient having type 2 diabetes mellitus orglucose intolerance and having failed surgery or who is not a candidatefor surgery; and other conditions associated with Cushing's syndrome.

“Treat”, “treating” and “treatment” refer to any indicia of success inthe treatment or amelioration of a pathology or condition, including anyobjective or subjective parameter such as abatement; remission;diminishing of symptoms or making the pathology or condition moretolerable to the patient; slowing in the rate of degeneration ordecline; making the final point of degeneration less debilitating; orimproving a patient's physical or mental well-being. The treatment oramelioration of symptoms can be based on objective or subjectiveparameters; including the results of a physical examination;histopathological examination (e.g., analysis of biopsied tissue);laboratory analysis of urine, saliva, tissue samples, serum, plasma, orblood; or imaging.

As used herein, “treating a patient who is suffering from Cushing'ssyndrome”, or treating a subject who is suffering from Cushing'ssyndrome”, or similar phrases refer to, without limitation, treating apatient suffering from Cushing's syndrome, including endogenousCushing's syndrome; treating a patient suffering from Cushing's Disease;or treating a patient suffering from a condition associated withCushing's syndrome. A condition associated with Cushing's syndrome isdiscussed above. For example, treating a patient who is suffering fromCushing's syndrome may include administering mifepristone or other GRAto control hyperglycemia secondary to hypercortisolism in adult patientswith endogenous Cushing's syndrome who have type 2 diabetes mellitus orglucose intolerance and have failed surgery or are not candidates forsurgery.

As used herein, the term “administration” refers to the delivery of adrug or other therapeutic into the body of a patient in need oftreatment by the drug or therapeutic, effective to achieve a therapeuticeffect. Administration may be by any suitable route of administration,including, for example, oral administration; intravenous administration;subcutaneous administration; parenteral administration; intra-arterialadministration; nasal administration; topical administration; and otherroutes of administration.

As used herein, the terms “percent”, “%” and “weight percent” whenapplied to a dosage administered to a subject, all refer to a percentagetaken by comparing the weight of a first dose to that of a second dose,and multiplying the resulting decimal fraction by 100. Thus, forexample, where an original mifepristone dose is 1200 milligrams (mg), adose that is reduced by 50% is a dose of 600 mg mifepristone; and wherean original mifepristone dose is 600 milligrams (mg), a dose that isreduced by 50% is a dose of 300 mg mifepristone; and so forth.

As used herein, the phrases “less than x by at least”, “less than x byat least about”, and the like refer to amounts equal to and less thanthe x, where x is a number. For example, the phrase “less than theoriginal dosage by at least 25%” refers to dosage amounts that include25% less than the original dosage as well as other percentages (e.g.,26%, 28%, etc.) less than the original dosage amount.

As used herein, the terms “effective amount,” “amounts effective,”therapeutic amount”, and “therapeutically effective amount” refer to anamount or amounts of one or more pharmacological agents effective totreat, eliminate, or mitigate at least one symptom of the disease beingtreated. In some cases, “effective amount,” “amounts effective,”“therapeutic amount”, and “therapeutically effective amount” can referto an amount of a functional agent or of a pharmaceutical compositionuseful for exhibiting a detectable therapeutic or inhibitory effect.

As used herein, the term “simultaneously or sequentially administering”refers to administration of two compounds, such as a GRA and a CYP3Ainhibitor, such that the two compounds are in the body at the same timein therapeutically effective amounts.

As used herein, “concomitant” means at the same, or nearly the same,time, and “concomitantly” refers to actions performed at the same, ornearly the same, time. As used herein, the terms “concurrent” and“concomitant” are equivalent and may be used interchangeably. Theadverbs “concurrently” and “concomitantly” are equivalent and may beused interchangeably.

As used herein, the term “concomitant administration” of two or moredrugs means administering two or more drugs at the same, or nearly thesame, time. Concomitant administration of two or more drugs providestherapeutically effective amounts of the two or more drugs in the systemof the subject at the same time. Concomitant administration includesadministration of a GRA to a patient who has previously beenadministered a drug, such as a CYP3A inhibitor or a steroidogenesisinhibitor, and therapeutically effective levels of the CYP3A inhibitoror steroidogenesis inhibitor remain in the patient when the patient isadministered the GRA (e.g., when the patient is administeredmifepristone), and includes administration of a CYP3A inhibitor or asteroidogenesis inhibitor to a patient who has previously beenadministered a drug, such as a GRA, and therapeutically effective levelsof the GRA remain in the patient when the patient is administered theCYP3A inhibitor or steroidogenesis inhibitor.

As used herein, “concomitantly administering drugs” means that two ormore drugs are administered to a subject at the same, or nearly thesame, time. Drugs that are concomitantly administered will each bepresent in therapeutically effective amounts in the system of thesubject at the same time. Nearly the same time means that only a shortamount of time separates two events, such as administration of a firstdrug and the administration of a second drug.

Events or actions that are “simultaneous” or that occur or are performed“simultaneously” are events that occur or are performed at the sametime.

As used herein, “at the same time” means that two events occur or areperformed within about five minutes of each other.

As used herein, “nearly the same time” means that two events occur orare performed within about a short time of each other.

As used herein, a “short time”, a “short amount of time”, a “shortperiod of time”, and the like mean a time that is less than about twohours, or less than about one hour, or less than about 45 minutes, orless than about 30 minutes, or less than about 20 minutes, or less thanabout 10 minutes, or less than about 7 minutes.

As used herein, the term “clinical effect” means changes in symptoms orsigns characteristic of, or indicative of, a clinical condition ordisorder. For example, where a subject is treated for Cushing'ssyndrome, including Cushing's Disease, a clinical effect may be a changein any one or more of blood pressure, blood glucose, other pre-diabeticsymptom, weight, mid-section perimeter, facial characteristics (e.g.,change in “moon-face” appearance), immune function, skin thickness,acne, depression or other mood symptom, hirsutism, and other symptoms.

As used herein, “monitoring for clinical response”, e.g., monitoring apatient for clinical response to a GRA such as mifepristone, may includemonitoring the patient (e.g., to identify or determine if there arechanges in) for glucose control, anti-diabetic medication requirement,insulin level, psychiatric symptoms, cushingoid appearance, acne,hirsutism, and monitoring the body weight of the patient (e.g., toidentify or determine if there are changes in any one or more of thesesymptoms and characteristics). Monitoring for clinical response may alsoinclude monitoring a patient for adverse events, for side-effects of anydrug (including a GRA, a CYP3A inhibitor, a steroidogenesis inhibitor,and combinations of these). Thus, monitoring for clinical response mayinclude monitoring for clinical effect of a drug such as a GRM,including clinical efficacy of the GRM; for clinical effect of asteroidogenesis inhibitor or CYP3A inhibitor; for possible adversereaction to a steroidogenesis inhibitor or CYP3A inhibitor; for possibleadverse reaction to the use of a steroidogenesis inhibitor or CYP3Ainhibitor in combination with the GRM; for possible side-effects of asteroidogenesis inhibitor or CYP3A inhibitor, or their use incombination with the GRM; or combinations thereof.

As used herein, the term “AUC” means the area under the plasmaconcentration-time curve, and serves as a measure of the plasma levelsof a drug in a subject to whom the drug has been administered.

As used herein, the term “C_(max)” means the maximum observed plasmaconcentration of a drug in a subject to whom the drug has beenadministered.

As used herein, the term “binding” refers to persistent contact, oradherence (however brief or intermittent), between two compounds.

As used herein, the terms “affinity”, “binding affinity”, and relatedterms refer to the strength and specificity of binding, such as bindingbetween a ligand and its receptor. “Higher affinity” is used withreference to comparative binding between two ligands to a receptor,where the ligand which binds with higher affinity binds at a lowerconcentration than does the “lower affinity” ligand. For example, in acompetitive binding experiment, a high affinity ligand will compete witha reference ligand for binding to a receptor at a lower concentrationthan will the low affinity ligand compete for binding at the receptor.

The term “specific binding” refers to binding that is more selective,and typically stronger, than mere non-specific adhesion betweencompounds. Specific binding may be exemplified by the binding whichoccurs between a ligand and its receptor.

Description of compounds useful in the methods disclosed herein, andsuitable for the pharmaceutical compositions disclosed herein aredescribed in accordance with principles of chemical bonding known tothose skilled in the art. Accordingly, where a group may be substitutedby one or more of a number of substituents, such substitutions areselected so as to comply with principles of chemical bonding and to givecompounds which are not inherently unstable and/or would be known to oneof ordinary skill in the art as likely to be unstable under ambientconditions, such as aqueous, neutral, or physiological conditions.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

“Alkyl” refers to a straight or branched, saturated, aliphatic radicalhaving the number of carbon atoms indicated. Alkyl can include anynumber of carbons, such as C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₁₋₆, C₁₋₇, C₁₋₈,C₁₋₉, C₁₋₁₀, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₃₋₄, C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆ andC₅₋₆. For example, C₁₋₆ alkyl includes, but is not limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, hexyl, etc.

“Alkoxy” refers to an alkyl group having an oxygen atom that connectsthe alkyl group to the point of attachment: alkyl-O—. As for the alkylgroup, alkoxy groups can have any suitable number of carbon atoms, suchas C₁₋₆. Alkoxy groups include, for example, methoxy, ethoxy, propoxy,iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,pentoxy, hexoxy, etc.

“Halogen” refers to fluorine, chlorine, bromine and iodine.

“Haloalkyl” refers to alkyl, as defined above, where some or all of thehydrogen atoms are replaced with halogen atoms. As for the alkyl group,haloalkyl groups can have any suitable number of carbon atoms, such asC₁₋₆. For example, haloalkyl includes trifluoromethyl, fluoromethyl,etc. In some instances, the term “perfluoro” can be used to define acompound or radical where all the hydrogens are replaced with fluorine.For example, perfluoromethane includes 1,1,1-trifluoromethyl.

“Haloalkoxy” refers to an alkoxy group where some or all of the hydrogenatoms are substituted with halogen atoms. As for the alkyl group,haloalkoxy groups can have any suitable number of carbon atoms, such asC₁₋₆. The alkoxy groups can be substituted with 1, 2, 3, or morehalogens. When all the hydrogens are replaced with a halogen, forexample by fluorine, the compounds are per-substituted, for example,perfluorinated. Haloalkoxy includes, but is not limited to,trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, etc.

“Cycloalkyl” refers to a saturated or partially unsaturated, monocyclic,fused bicyclic or bridged polycyclic ring assembly containing from 3 to12 ring atoms, or the number of atoms indicated. Cycloalkyl can includeany number of carbons, such as C₃₋₆, C₄₋₆, C₅₋₆, C₃₋₈, C₄₋₈, C₅₋₈, C₆₋₈,C₃₋₉, C₃₋₁₀, C₃₋₁₁, and C₃₋₁₂. Saturated monocyclic cycloalkyl ringsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl ringsinclude, for example, norbornane, [2.2.2] bicyclooctane,decahydronaphthalene and adamantane. Cycloalkyl groups can also bepartially unsaturated, having one or more double or triple bonds in thering. Representative cycloalkyl groups that are partially unsaturatedinclude, but are not limited to, cyclobutene, cyclopentene, cyclohexene,cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene,cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene,and norbornadiene. When cycloalkyl is a saturated monocyclic C₃₋₈cycloalkyl, exemplary groups include, but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl. When cycloalkyl is a saturated monocyclic C₃₋₆ cycloalkyl,exemplary groups include, but are not limited to cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Heterocycloalkyl” refers to a saturated ring system having from 3 to 12ring members and from 1 to 4 heteroatoms of N, O and S. Additionalheteroatoms can also be useful, including, but not limited to, B, Al, Siand P. The heteroatoms can also be oxidized, such as, but not limitedto, —S(O)— and —S(O)₂—. Heterocycloalkyl groups can include any numberof ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8,6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitablenumber of heteroatoms can be included in the heterocycloalkyl groups,such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3to 4. The heterocycloalkyl group can include groups such as aziridine,azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine,pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers),oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane,thiirane, thietane, thiolane (tetrahydrothiophene), thiane(tetrahydrothiopyran), oxazolidine, isoxalidine, thiazolidine,isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine,dioxane, or dithiane. The heterocycloalkyl groups can also be fused toaromatic or non-aromatic ring systems to form members including, but notlimited to, indoline.

When heterocycloalkyl includes 3 to 8 ring members and 1 to 3heteroatoms, representative members include, but are not limited to,pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene,thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine,isoxazolidine, thiazolidine, isothiazolidine, morpholine,thiomorpholine, dioxane and dithiane. Heterocycloalkyl can also form aring having 5 to 6 ring members and 1 to 2 heteroatoms, withrepresentative members including, but not limited to, pyrrolidine,piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine,imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine,isothiazolidine, and morpholine.

“Aryl” refers to an aromatic ring system having any suitable number ofring atoms and any suitable number of rings. Aryl groups can include anysuitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14,15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ringmembers. Aryl groups can be monocyclic, fused to form bicyclic ortricyclic groups, or linked by a bond to form a biaryl group.Representative aryl groups include phenyl, naphthyl and biphenyl. Otheraryl groups include benzyl, having a methylene linking group. Some arylgroups have from 6 to 12 ring members, such as phenyl, naphthyl orbiphenyl. Other aryl groups have from 6 to 10 ring members, such asphenyl or naphthyl. Some other aryl groups have 6 ring members, such asphenyl. Aryl groups can be substituted or unsubstituted.

“Heteroaryl” refers to a monocyclic or fused bicyclic or tricyclicaromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5of the ring atoms are a heteroatom such as N, O or S. Additionalheteroatoms can also be useful, including, but not limited to, B, Al, Siand P. The heteroatoms can also be oxidized, such as, but not limitedto, N-oxide, —S(O)— and —S(O)₂—. Heteroaryl groups can include anynumber of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Anysuitable number of heteroatoms can be included in the heteroaryl groups,such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring membersand from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms.The heteroaryl group can include groups such as pyrrole, pyridine,imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine,pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene,furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroarylgroups can also be fused to aromatic ring systems, such as a phenylring, to form members including, but not limited to, benzopyrroles suchas indole and isoindole, benzopyridines such as quinoline andisoquinoline, benzopyrazine (quinoxaline), benzopyrimidine(quinazoline), benzopyridazines such as phthalazine and cinnoline,benzothiophene, and benzofuran. Other heteroaryl groups includeheteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groupscan be substituted or unsubstituted.

The heteroaryl groups can be linked via any position on the ring. Forexample, pyrrole includes 1-, 2- and 3-pyrrole, pyridine includes 2-, 3-and 4-pyridine, imidazole includes 1-, 2-, 4- and 5-imidazole, pyrazoleincludes 1-, 3-, 4- and 5-pyrazole, triazole includes 1-, 4- and5-triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes2-, 4-, 5- and 6-pyrimidine, pyridazine includes 3- and 4-pyridazine,1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-,5- and 6-triazine, 1,3,5-triazine includes 2-triazine, thiopheneincludes 2- and 3-thiophene, furan includes 2- and 3-furan, thiazoleincludes 2-, 4- and 5-thiazole, isothiazole includes 3-, 4- and5-isothiazole, oxazole includes 2-, 4- and 5-oxazole, isoxazole includes3-, 4- and 5-isoxazole, indole includes 1-, 2- and 3-indole, isoindoleincludes 1- and 2-isoindole, quinoline includes 2-, 3- and 4-quinoline,isoquinoline includes 1-, 3- and 4-isoquinoline, quinazoline includes 2-and 4-quinoazoline, cinnoline includes 3- and 4-cinnoline,benzothiophene includes 2- and 3-benzothiophene, and benzofuran includes2- and 3-benzofuran.

Some heteroaryl groups include those having from 5 to 10 ring membersand from 1 to 3 ring atoms including N, O or S, such as pyrrole,pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine,pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene,furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, and benzofuran. Other heteroaryl groupsinclude those having from 5 to 8 ring members and from 1 to 3heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole,pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, andisoxazole. Some other heteroaryl groups include those having from 9 to12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole,quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine,cinnoline, benzothiophene, benzofuran and bipyridine. Still otherheteroaryl groups include those having from 5 to 6 ring members and from1 to 2 ring heteroatoms including N, O or S, such as pyrrole, pyridine,imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan,thiazole, isothiazole, oxazole, and isoxazole.

Some heteroaryl groups include from 5 to 10 ring members and onlynitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole,triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline,quinazoline, phthalazine, and cinnoline. Other heteroaryl groups includefrom 5 to 10 ring members and only oxygen heteroatoms, such as furan andbenzofuran. Some other heteroaryl groups include from 5 to 10 ringmembers and only sulfur heteroatoms, such as thiophene andbenzothiophene. Still other heteroaryl groups include from 5 to 10 ringmembers and at least two heteroatoms, such as imidazole, pyrazole,triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline,quinazoline, phthalazine, and cinnoline.

“Heteroatoms” refers to O, S or N.

“Salt” refers to acid or base salts of the compounds used in the methodsof the present invention. Illustrative examples of pharmaceuticallyacceptable salts are mineral acid (hydrochloric acid, hydrobromic acid,phosphoric acid, and the like) salts, organic acid (acetic acid,propionic acid, glutamic acid, citric acid and the like) salts,quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.It is understood that the pharmaceutically acceptable salts arenon-toxic. Additional information on suitable pharmaceuticallyacceptable salts can be found in Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa., 1985, which isincorporated herein by reference.

“Isomers” refers to compounds with the same chemical formula but whichare structurally distinguishable.

“Tautomer” refers to one of two or more structural isomers which existin equilibrium and which are readily converted from one form to another.

As used herein, the term “ketoconazole” refers to the molecule havingthe chemical name“1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)-methyl]-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine)”;it is sold for clinical use under the name “Nizoral”, and may also bereferred to by the abbreviation “keto”.

As used herein, the terms “steroid” and “steroids”, and the phrase“steroidal backbone” in the context of glucocorticoid receptorantagonists containing such refers to glucocorticoid receptorantagonists that contain modifications of the basic structure ofcortisol, an endogenous steroidal glucocorticoid receptor ligand. Thebasic structure of a steroidal backbone is provided as Formula I:

The two most commonly known classes of structural modifications of thecortisol steroid backbone to create glucocorticoid antagonists includemodifications of the 11-β hydroxy group and modification of the 17-βside chain (See, e.g., Lefebvre (1989) J. Steroid Biochem. 33: 557-563).

As used herein, the terms “progesterone receptor” and “PR” refer to anaturally occurring receptor which binds progesterone.

The term “aldosterone” refers to the naturally occurringmineralocorticoid hormone having the structure:

A mineralocorticoid receptor (MR), also known as a type I glucocorticoidreceptor (GR I), is activated by aldosterone in humans.

The term “cortisol” refers to the naturally occurring glucocorticoidhormone (also known as hydrocortisone) having the structure:

As used herein, the term glucocorticoid receptor (GR) refers to areceptor that binds a glucocorticoid, such as cortisol, dexamethasone,or other molecules. A glucocorticoid receptor, also known as acorticosteroid receptor or as a type II glucocorticoid receptor (GR II),and in humans, as a cortisol receptor, is activated by cortisol inhumans (or, e.g., by corticosterone (“cortisone”) in some other animals,such as rats and mice). The human cortisol receptor (GR II receptor,Genbank: P04150) specifically binds to cortisol and/or cortisol analogs(e.g. dexamethasone). The term includes isoforms of GR II, recombinantGRII, and mutated GRII.

As used herein, the term glucocorticoid receptor modulator (GRM) refersto an agent that affects the action of a glucocorticoid receptor (GR).Such modulation may include activation (agonist action), partialactivation (partial agonist action), inhibition (reduction in activationof the receptor under conditions where it would otherwise be activated,such as in the presence of cortisol), and blockade (complete or nearcomplete suppression of activation of the receptor under conditionswhere it would otherwise be activated, such as in the presence ofcortisol). GRMs may affect the activity of a GR by increasing or bydecreasing the activity of the GR. GRMs include steroids, and, inembodiments, include pyrimidinediones; azadecalins; fused-ringazadecalins; heteroaryl-ketone fused-ring azadecalins; and othercompounds.

As used herein, the terms “glucocorticoid agonist”, “glucocorticoidreceptor agonist”, “glucocorticoid receptor type II agonist”, and “GRIIagonist” refer to a compound or agent which may bind to and activate acortisol receptor. Such agents include, for example, cortisol,dexamethosone, prednisone, and other compounds and agents which bind toand activate a GRII.

As used herein, the terms “glucocorticoid antagonist”, “glucocorticoidreceptor antagonist”, “glucocorticoid antagonist”, “glucocorticoidreceptor type II antagonist”, “GRII antagonist”, and “GRA” refer toagents that inhibit the action of a cortisol receptor; such inhibitionmay include interfering with the binding of a glucocorticoid agonistsuch as cortisol, dexamethosone, or other compound or agent which maybind to and activate a cortisol receptor. A GRA is a glucocorticoidreceptor modulator. Inhibition constants (K_(i)) for GRAs against thehuman cortisol receptor may be between about 0.0001 nM and about 1,000nM; preferably may be between about 0.0005 nM and about 10 nM, and mostpreferably between about 0.001 nM and about 1 nM.

The term “glucocorticoid receptor antagonist” refers to any compositionor compound which partially or completely inhibits (antagonizes) thebinding of a glucocorticoid receptor (GR) agonist, such as cortisol, orcortisol analogs, synthetic or natural, to a GR. A “specificglucocorticoid receptor antagonist” refers to any composition orcompound which inhibits any biological response associated with thebinding of a GR to an agonist. By “specific,” we intend the drug topreferentially bind to the GR rather than another nuclear receptors,such as mineralocorticoid receptor (MR) or progesterone receptor (PR).

By “specific,” the drug preferentially binds to the GR rather than othernuclear receptors, such as mineralocorticoid receptor (MR), androgenreceptor (AR), or progesterone receptor (PR). It is preferred that thespecific glucocorticoid receptor antagonist bind GR with an affinitythat is 10× greater ( 1/10^(th) the K_(d) value) than its affinity tothe MR, AR, or PR. In a more preferred embodiment, the specificglucocorticoid receptor antagonist binds GR with an affinity that is100× greater ( 1/100^(th) the K_(d) value) than its affinity to the MR,AR, or PR.

In embodiments, a glucocorticoid receptor modulator (GRM) is aglucocorticoid receptor antagonist (GRA). In embodiments, the GRA is anantagonist of a glucocorticoid type II (GRII) receptor. In embodiments,the GRA binds preferentially to a GRII receptor as compared to itsbinding to a glucocorticoid type I (GRI) receptor. In embodiments, theGRA reduces the activation of a GRII receptor. In embodiments, the GRAreduces the activity of a GRII receptor. In embodiments, the GRA maybind to a progesterone receptor (PR), and may bind to a glucocorticoidreceptor with higher affinity than it binds to PR. In embodiments, theGRA is mifepristone. In embodiments, the GRA is a selective inhibitor ofthe glucocorticoid receptor. In embodiments, the GRA may only poorlybind to PR, or may not measurably bind to PR.

As used herein, a “steroidal glucocorticoid receptor antagonist” means amolecule including a steroid backbone structure which antagonizes thebinding of cortisol, corticosterone, or dexamethasone to aglucocorticoid receptor, or which reduces or blocks the activation of aglucocorticoid receptor by cortisol, corticosterone, or dexamethasone.Examples of steroidal glucocorticoid receptor antagonists includemifepristone, monodemethylated mifepristone, didemethylatedmifepristone, 17-α-[3′-hydroxy-propynyl]mifepristone, ulipristal(CDB-2914), CDB-3877, CDB-3963, CDB-3236, CDB-4183, cortexolone,dexamethasone-oxetanone, 19-nordeoxycorticosterone, 19-norprogesterone,cortisol-21-mesylate; dexamethasone-21-mesylate,11(-(4-dimethylaminoethoxyphenyl)-17(-propynyl-17(-hydroxy-4,9-estradien-3one,and 17(-hydroxy-17(-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one.

Mifepristone is a GRA, which binds to GRII (and which also binds to aprogesterone receptor). As used herein, the term “mifepristone” refersto11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(1-propynyl)-estra-4,9-dien-3-one),also referred to as RU1486, or as RU38,486, or as17-beta-hydroxy-11-beta-(4-dimethyl-aminophenyl)-17-alpha-(1-propynyl)-estra-4,9-dien-3-one).Mifepristone binds to the glucocorticoid receptor (GR), typically withhigh affinity, and inhibits the biological effects initiated/mediated bythe binding of any cortisol or cortisol analogue to a GR receptor.Salts, hydrates and prodrugs of mifepristone are all included in theterm “mifepristone” as used herein. Thus, used herein, “mifepristone”refers to the molecule that has the following structure:

and to salts, hydrates and prodrugs thereof, and pharmaceuticalcompositions thereof. Mifepristone is also sometimes abbreviated as“mife” and “MIFE”.

Metabolites of mifepristone include RU42633 (desmethylmifepristone:(8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-11-[4-(methylamino)phenyl]-17-prop-1-ynyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one);RU42698 (22-hydroxy mifepristone:(8S,11R,13S,14S,17S)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxyprop-1-ynyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one);and RU42848 (didesmethylmifepristone:(8S,11R,13S,14S,17S)-11-(4-aminophenyl)-17-hydroxy-13-methyl-17-prop-1-ynyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one),among others.

In some embodiments, the GRA comprises a steroidal backbone with atleast one phenyl-containing moiety in the 11-β position of the steroidalbackbone. In some cases, the phenyl-containing moiety in the 11-βposition of the steroidal backbone is a dimethylaminophenyl moiety. Insome cases, the GRA is mifepristone. In some embodiments, the GRA isselected from the group consisting of11β-(4-dimethylaminoethoxyphenyl)-17α-propynyl-17β-hydroxy-4,9estradien-3-one and(17α)-17-hydroxy-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one. In someembodiments, the GRA is(11β,17β)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one.

As used herein, the phrase “non-steroidal backbone” in the context ofglucocorticoid receptor antagonists containing such refers toglucocorticoid receptor antagonists that do not share structuralhomology to, or are not modifications of, cortisol. Such compoundsinclude, for example, small molecules, synthetic mimetics and analogs ofproteins, including partially peptidic, pseudopeptidic and non-peptidicmolecular entities.

In some embodiments, the GRA is a non-steroidal compound. Inembodiments, non-steroidal GRA compounds include compounds having acyclohexyl-pyrimidine backbone; non-steroidal GRA compounds having afused azadecalin backbone; non-steroidal GRA compounds having aheteroaryl ketone fused azadecalin backbone; and non-steroidal GRAcompounds having an octahydro fused azadecalin backbone. Exemplaryglucocorticoid receptor antagonists having a cyclohexyl-pyrimidinebackbone include those described in U.S. Pat. No. 8,685,973. Exemplaryglucocorticoid receptor antagonists having a fused azadecalin backboneinclude those described in U.S. Pat. Nos. 7,928,237; and 8,461,172.Exemplary glucocorticoid receptor antagonists having a heteroaryl ketonefused azadecalin backbone include those described in U.S. Pat. No.8,859,774. Exemplary glucocorticoid receptor antagonists having anoctahydro fused azadecalin backbone include those described in U.S.Patent Application Publication 20150148341.

In some cases, the GRA having a non-steroidal backbone is a cyclohexylpyrimidine. In some cases, wherein the cyclohexyl pyrimidine has thefollowing formula:

wherein the dashed line is absent or a bond; X is selected from thegroup consisting of O and S; R¹ is selected from the group consisting ofcycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionallysubstituted with from 1 to 3 R^(1a) groups; each R^(1a) is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkyl OR^(1b), halogen, C₁₋₆ haloalkyl, C₁₋₆haloaloxy, OR^(1b), NR^(1b)R^(1c), C(O)R^(1b), C(O)OR^(1b), OC(O)R^(1b),C(O)NR^(1b)R^(1c), NR^(1b)C(O)R^(1c), SO₂R^(1b), SO₂NR^(1b)R^(1c),cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R^(1b) and R^(1c) areeach independently selected from the group consisting of H and C₁₋₆alkyl; R² is selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆alkyl-OR^(1b), C₁₋₆ alkyl NR^(1b)R^(1c) and C₁₋₆ alkyleneheterocycloalkyl; R³ is selected from the group consisting of H and C₁₋₆alkyl; Ar is aryl, optionally substituted with 1-4 R⁴ groups; each R⁴ isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆alkoxy, halogen, C₁₋₆ haloalkyl and C₁₋₆ haloalkoxy; L¹ is a bond orC₁₋₆ alkylene; and subscript n is an integer from 0 to 3, or salts andisomers thereof.

In some cases, the GRA having a non-steroidal backbone is a fusedazadecalin. In some cases, the fused azadecalin is a compound having thefollowing formula:

wherein L¹ and L² are members independently selected from a bond andunsubstituted alkylene; R¹ is a member selected from unsubstitutedalkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl,—OR^(1A), NR^(1C)R^(1D), —C(O)NR^(1C)R^(1D), and —C(O)OR^(1A), whereinR^(1A) is a member selected from hydrogen, unsubstituted alkyl andunsubstituted heteroalkyl, R^(1C) and R^(1D) are members independentlyselected from unsubstituted alkyl and unsubstituted heteroalkyl, whereinR^(1C) and R^(1D) are optionally joined to form an unsubstituted ringwith the nitrogen to which they are attached, wherein said ringoptionally comprises an additional ring nitrogen; R² has the formula:

wherein R^(2G) is a member selected from hydrogen, halogen,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, —CN, and —CF₃; J is phenyl;t is an integer from 0 to 5; X is —S(O₂)—; and R⁵ is phenyl optionallysubstituted with 1-5 R^(5A) groups, wherein R^(5A) is a member selectedfrom hydrogen, halogen, —OR^(5A1), S(O₂)NR^(5A2)R^(5A3), —CN, andunsubstituted alkyl, wherein R^(5A1) is a member selected from hydrogenand unsubstituted alkyl, and R^(5A2) and R^(5A3) are membersindependently selected from hydrogen and unsubstituted alkyl, or saltsand isomers thereof.

In some cases, the GRA having a non-steroidal backbone is a heteroarylketone fused azadecalin or an octahydro fused azadecalin. In some cases,the heteroaryl ketone fused azadecalin has the formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, CN, N-oxide, C₃₋₈ cycloalkyl, and C₃₋₈heterocycloalkyl; ring J is selected from the group consisting of acycloalkyl ring, a heterocycloalkyl ring, an aryl ring and a heteroarylring, wherein the heterocycloalkyl and heteroaryl rings have from 5 to 6ring members and from 1 to 4 heteroatoms each independently selectedfrom the group consisting of N, O and S; each R² is independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₆ haloalkyl, C₁ ₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkyl-C₁₋₆ alkoxy, CN,OH, NR^(2a)R^(2b), C(O)R^(2a), C(O)OR^(2a), C(O)NR^(2a)R^(2b), SR^(2a),S(O)R^(2a), S(O)₂R^(2a), C₃₋₈ cycloalkyl, and C₃₋₈ heterocycloalkyl,wherein the heterocycloalkyl groups are optionally substituted with 1-4R^(2c) groups; alternatively, two R² groups linked to the same carbonare combined to form an oxo group (═O); alternatively, two R² groups arecombined to form a heterocycloalkyl ring having from 5 to 6 ring membersand from 1 to 3 heteroatoms each independently selected from the groupconsisting of N, O and S, wherein the heterocycloalkyl ring isoptionally substituted with from 1 to 3 R^(2d) groups; R^(2a) and R^(2b)are each independently selected from the group consisting of hydrogenand C₁₋₆ alkyl; each R^(2c) is independently selected from the groupconsisting of hydrogen, halogen, hydroxy, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,CN, and NR^(2a)R^(2b); each R^(2d) is independently selected from thegroup consisting of hydrogen and C₁₋₆ alkyl, or two R^(2d) groupsattached to the same ring atom are combined to form (═O); R³ is selectedfrom the group consisting of phenyl and pyridyl, each optionallysubstituted with 1-4 R^(3a) groups; each R^(3a) is independentlyselected from the group consisting of hydrogen, halogen, and C₁₋₆haloalkyl; and subscript n is an integer from 0 to 3; or salts andisomers thereof.

In some cases, the octahydro fused azadecalin has the formula:

wherein R¹ is a heteroaryl ring having from 5 to 6 ring members and from1 to 4 heteroatoms each independently selected from the group consistingof N, O and S, optionally substituted with 1-4 groups each independentlyselected from R^(1a); each R^(1a) is independently selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, N-oxide, and C₃₋₈ cycloalkyl; ring J isselected from the group consisting of an aryl ring and a heteroaryl ringhaving from 5 to 6 ring members and from 1 to 4 heteroatoms eachindependently selected from the group consisting of N, O and S; each R²is independently selected from the group consisting of hydrogen, C₁₋₆alkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆alkyl-C₁₋₆ alkoxy, CN, OH, NR^(2a)R^(2b), C(O)R^(2a), C(O)OR^(2a),C(O)NR^(2a)R^(2b), SR^(2a), S(O)R^(2a), S(O)₂R^(2a), C₃₋₈ cycloalkyl,and C₃₋₈ heterocycloalkyl having from 1 to 3 heteroatoms eachindependently selected from the group consisting of N, O and S;alternatively, two R² groups on adjacent ring atoms are combined to forma heterocycloalkyl ring having from 5 to 6 ring members and from 1 to 3heteroatoms each independently selected from the group consisting of N,O and S, wherein the heterocycloalkyl ring is optionally substitutedwith from 1 to 3 R^(2c) groups; R^(2a), R^(2b) and R^(2c) are eachindependently selected from the group consisting of hydrogen and C₁₋₆alkyl; each R^(3a) is independently halogen; and subscript n is aninteger from 0 to 3, or salts and isomers thereof.

Further examples of non-steroidal glucocorticoid receptor antagonistsinclude, for example N-(2-[4,4′,441-trichlorotrityl]oxyethyl)morpholine;1-(2[4,4′,4″-trichlorotrityl]oxyethyl)-4-(2-hydroxyethyl)piperazinedimaleate; N-([4,4′,4″]-trichlorotrityl)imidazole;9-(3-mercapto-1,2,4-triazolyl)-9-phenyl-2,7-difluorofluorenone;1-(2-chlorotrityl)-3,5-dimethylpyrazole;4-(morpholinotnethyl)-A-(2-pyridyl)benzhydrol;5-(5-methoxy-2-(N-methylcarbamoyl)-phenyl)dibenzosuberol;N-(2-chlorotrityl)-L-prolinol acetate;1-(2-chlorotrityl)-1,2,4-triazole;1,S-bis(4,4′,4″-trichlorotrityl)-1,2,4-triazole-3-thiol;4α(S)-Benzyl-2(R)-chloroethynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-diol(“CP 394531”),4α(S)-Benzyl-2(R)-prop-1-ynyl-1,2,3,4,4α,9,10,10α(R)octahydro-phenanthrene-2,7-diol(“CP-409069”), trans-(1R,2R)-3,4-dichloro-N-methyl-N-[2-1pyrrolidinyl)cyclohexyl]benzeneacetamide, bremazocine, andethylketocyclazocine.

As used herein, the term “hormone-sensitive cancer” refers to any cancerWhich may be affected by a hormone; hormones typically increaseproliferation of hormone-sensitive cancers. Hormone sensitive cancersinclude, e.g., prostate cancer and other androgen-sensitive cancers;breast cancer, ovarian cancer and other estrogen-sensitive orprogesterone-sensitive cancers.

As used herein, the term “chemotherapy” refers to medical treatmentstypically used to treat cancer. Chemotherapy treatments include the useof agents which are toxic to cancerous tissues and cells, or which actto slow or reduce the growth or spread of cancerous tissues and cells.Chemotherapy agents include antineoplastic agents and may be derivedfrom natural compounds (e.g., taxols); may be, may mimic, or may reduceor block the actions of naturally occurring hormones, growth factors, orimmunologically active molecules; may be synthetic small molecules; maybe antibodies or antibody conjugates; and may be other agents. Exemplarychemotherapy agents include, but are not limited to, taxanes, taxol,docetaxel, paclitaxel, actinomycin, anthracyclines, doxorubicin,daunorubicin, valrubicin, bleomycin, cisplatin, trastuzumab(Herceptin®), trastuzumab emtasine (Kadcyla®), imatinib (Gleevec®),eribulin (Halaven®), among others known in the art.

As used herein, a phrase of the form “the reduced dose of Z is a dosethat is at least about X % less than the original dose” (where “Z”represents a pharmaceutical compound or pharmaceutical composition, and“X” represents a numerical value) is used to indicate that the reduceddose is an amount of Z calculated by 1) multiplying the amount of Z inthe original dose by X % to obtain a multiplicative product, and 2)subtracting that product from the original dose. Thus, for example,where the original dose is 600 mg, and X % is 50%, the multiplicativeproduct of 600 mg and 50% is 300 mg, and the reduced dose is 300 mg;and, for example, where the original dose is 900 mg, and X % is 66%, themultiplicative product of 900 mg and 66% is about 600 mg (594 mg), andthe reduced dose is about 300 mg (306 mg).

As used herein, the terms “pharmaceutical composition” and “formulation”refer to compositions suitable for administration to a patient fortreatment of a medical condition or for amelioration of symptoms of amedical condition. A pharmaceutical composition as disclosed hereinincludes an active ingredient (e.g., a GRA, such as, e.g., mifepristone;or a combination of a GRA and a SI, where the SI may be, e.g.,ketoconazole) and a pharmaceutically acceptable excipient. Inembodiments, a pharmaceutical composition includes one or more activeingredients and one or more pharmaceutically acceptable excipients.

As used herein, the terms “pharmaceutically acceptable excipient” and“pharmaceutically acceptable carrier” refer to a substance that aids theadministration of an active agent to and absorption by a subject and canbe included in the compositions of the present invention without causinga significant adverse toxicological effect on the patient. Non-limitingexamples of pharmaceutically acceptable excipients include water, NaCl,normal saline solutions, lactated Ringer's, normal sucrose, normalglucose, binders, fillers, disintegrants, lubricants, coatings,sweeteners, flavors and colors, and the like. One of skill in the artwill recognize that other pharmaceutical excipients are useful in thepresent invention.

As used herein, the terms “sustained release,” “slow release,” “longacting,” “prolonged release,” and the like refer to a pharmaceuticalcomposition or formulation containing at least one active ingredient(e.g., GRA, SI, or combination thereof) formulated to maintain atherapeutic concentration of active ingredient(s) in a patient for alonger period of time in comparison to formulations that are notdesigned for such sustained release. In some cases, the sustainedrelease formulation maintains therapeutic concentration of one or moreactive ingredient(s) for, or for at least, one week, two weeks, threeweeks, four weeks, five weeks, or six weeks. In some cases, thesustained release formulation is administered to a patient every one,two, three, four, five, or six weeks.

As used herein, a “steroidogenesis inhibitor” is a compound whichreduces or blocks the synthesis of steroid molecules when administeredto an animal, or subject, which normally produces steroids.Steroidogenesis inhibitors include, for example, ketoconazole,metyrapone, etomidate, and other drugs. A steroidogenesis inhibitor mayact by one or more of several mechanisms, including, e.g., blockingsynthesis of steroid molecules (e.g., ketoconazole, metyrapone).

As used herein, the term “CYP enzyme” refers to a cytochrome P450enzyme. Cytochrome P450 enzymes are important in many metabolic andcatabolic reactions in humans and other animals, and play importantroles in drug metabolism and action. Drug-drug interactions in whichadministration of one drug affects the concentration, half-life,activity, or other effect of another drug may include effects on CYPenzymes by induction of CYP enzymes (increasing the amount or activityof one or more CYP enzymes); inhibition (reducing the activity of one ormore CYP enzymes); competition (competing for sites or occupying sites,e.g., as a substrate, of one or more CYP enzymes); or by other means.Particular CYP enzymes include, for example, CYP1A2, CYP2C9, CYP2C19,CYP2D6, and CYP3A enzymes.

As used herein, a “CYP3A inhibitor” is a compound which reduces orblocks the activity of the cytochrome CYP3A, or reduces or blocks theexpression of the gene-product of CYP3A genes (e.g., inhibitstranscription or translation of CYP3A genes). CYP3A inhibitors may betermed strong or moderate if their administration, along with a testdrug known to be metabolized by CYP3A enzymes (such as, e.g.,midazolam), raises the AUC (area under the concentration curve) of thetest drug by greater than five-fold (strong CYP3A inhibitors) or bybetween two-fold and five-fold (moderate CYP3A inhibitors). Inhibitorsof CYP3A include, for example, ketoconazole, itraconazole, fluconazole,cimetidine, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir,amprenavir, fosamprenavir, boceprevir, clarithromycin, conivaptan,lopinavir, posaconazole, saquinavir, telaprevir, telithromycin, andvoriconazole.

Strong CYP3A inhibitors include, for example, ketoconazole,itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir,amprenavir and fosamprenavir, clarithromycin, conivaptan,lopinavieritonavir, posaconazole, saquinavir, telithromycin, andvoriconazole.

Metyrapone (also known as Metopirone®) is2-methyl-1,2-bis-(3-pyridyl)-1-propanone. Metopirone is believed toreduce cortisol and corticosterone production by inhibiting the11-β-hydroxylation reaction in the adrenal cortex.

Etomidate (also known as Amidate®) isR-(+)-ethyl-1-(1-phenylethyl)-1H-imidazole-5-carboxylate. Althoughprimarily used as a rapid-onset anesthetic, etomidate also lowers plasmacortisol levels. It is believed to reduce corticosteroid synthesis inthe adrenal cortex by inhibiting 11β-hydroxylase.

Ketoconazole(1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)-methyl]-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine)is often used to treat fungal infections (e.g., (NIZORAL®) for thetreatment of fungal infections). In addition, ketoconazole is asteroidogenesis inhibitor and can reduce the production of steroidmolecules (such as, e.g., steroid hormones), typically by blocking themetabolism of cholesterol. Ketoconazole thus may be used to treatexcessive cortisol production (e.g., to treat Cushing's disease andCushing's syndrome), to reduce androgen production (e.g., in patientswith hormone-sensitive cancers such as prostate cancer), to reduceestrogen or progesterone production (e.g., in patients withhormone-sensitive cancers such as breast cancer), and other treatments.

However, ketoconazole often has serious deleterious effects on liver andother organs. Thus, it is desirable to minimize the dose of ketoconazoleadministered to a patient, and methods for reducing the dose ofketoconazole are desired.

Treatment Methods

Methods disclosed herein include methods of treating a diseasecharacterized by excess steroid levels, or by excess activity due tosteroids. Methods disclosed herein also include methods of treating adisease that may be treated by reducing or blocking the action ofsteroids, such as steroid hormones. In embodiments, the disease ischaracterized by excess cortisol such as, e.g., Cushing's syndrome, andin particular, Cushing's Disease. (As noted above, both Cushing'ssyndrome and Cushing's Disease are characterized by excess cortisol;Cushing's Disease falls within the definition of Cushing's syndrome as aparticular type or example of Cushing's syndrome; thus, all discussionand disclosure regarding Cushing's syndrome includes Cushing's Disease.)Methods disclosed herein also include methods of treating cancer andcancerous tumors, such as hormone-sensitive cancers including prostatecancer, comprising concomitant administration of a GRM and ketoconazoleto provide thereby beneficial therapeutic effects. Methods,compositions, and kits disclosed herein are related to the methodscompositions, and kits and compositions disclosed in U.S. ProvisionalPatent Application Ser. No. 62/465,772, filed Mar. 1, 2017, and U.S.Provisional Patent Application Ser. No. 62/466,867, filed Mar. 3, 2017,which applications are hereby incorporated by reference in theirentireties.

For example, the present methods include concomitantly administering toa patient a CYP3A inhibitor and a glucocorticoid receptor modulator(GRM), such as a glucocorticoid receptor antagonist (GRA). Inembodiments, the CYP3A inhibitor is ketoconazole. In embodiments, theCYP3A inhibitor is ketoconazole and the GRA is mifepristone. Inembodiments, the patient is receiving a CYP3A inhibitor (such as, e.g.,ketoconazole) and is concomitantly administered an amount of a GRA (suchas, e.g., mifepristone) effective to treat Cushing's syndrome, e.g.,effective to control hyperglycemia secondary to hypercortisolism in anadult patient suffering from endogenous Cushing's syndrome. Inembodiments, the adult patient suffering from endogenous Cushing'ssyndrome has type 2 diabetes mellitis or glucose intolerance. Inembodiments, the adult patient suffering from endogenous Cushing'ssyndrome has failed surgery or is not a candidate for surgery (e.g.,referring to surgical treatment for Cushing's syndrome). In embodiments,the adult patient suffering from endogenous Cushing's syndrome has type2 diabetes mellitis or glucose intolerance and has failed surgery or isnot a candidate for surgery (e.g., referring to surgical treatment forCushing's syndrome).

In embodiments, the present methods include methods for treatingCushing's syndrome in a patient taking a GRA, comprising reducing thedaily dosage amount of the GRA from an original GRA dose to an adjustedGRA dose when the patient is receiving concomitant administration of aCYP3A inhibitor. In embodiments, the adjusted dose of GRA is at least25% less than the original dose. In embodiments, the adjusted dose ofGRA is at least 33% less than the original dose. In embodiments, theadjusted dose of GRA is less than the original dose by a fraction of theoriginal dose selected from 10%, 20%, 25%, 30%, 33%, 33^(1/3)%, and 50%.In embodiments, the GRA is mifepristone, and the adjusted mifepristonedose is selected from 300 mg per day, 600 mg per day, and 900 mg perday. In embodiments, the CYP3A inhibitor is ketoconazole. Inembodiments, the CYP3A inhibitor is ketoconazole and the GRA ismifepristone. In embodiments, the patient is receiving a CYP3A inhibitor(such as, e.g., ketoconazole) and is concomitantly administered anamount of a GRA (such as, e.g., mifepristone) effective to treatCushing's syndrome, e.g., effective to control hyperglycemia secondaryto hypercortisolism in an adult patient suffering from endogenousCushing's syndrome. In embodiments, the adult patient suffering fromendogenous Cushing's syndrome has type 2 diabetes mellitis or glucoseintolerance. In embodiments, the adult patient suffering from endogenousCushing's syndrome has failed surgery or is not a candidate for surgery(e.g., referring to surgical treatment for Cushing's syndrome). Inembodiments, the adult patient suffering from endogenous Cushing'ssyndrome has type 2 diabetes mellitis or glucose intolerance and hasfailed surgery or is not a candidate for surgery (e.g., referring tosurgical treatment for Cushing's syndrome).

For example, the present disclosed methods include administering to apatient receiving ketoconazole an effective amount of a glucocorticoidreceptor modulator (GRM), such as a glucocorticoid receptor antagonist(GRA). In embodiments, the patient is receiving ketoconazole. Inembodiments, the patient is receiving ketoconazole and the GRA ismifepristone. In embodiments, the patient is receiving ketoconazole andis administered an amount of mifepristone effective to reduce the effectof a steroid such as cortisol in the patient.

Thus, in embodiments, the methods disclosed herein include a method fortreating a patient who is receiving ketoconazole treatment for excesssteroid levels, said ketoconazole treatment comprising administering anoriginal dose of ketoconazole to said patient, said method comprising:administering a GRA to the patient receiving ketoconazole, whereby thepatient receiving ketoconazole is administered a GRA for treating excesssteroid levels. In embodiments, the GRA is mifepristone. In embodiments,the disease is Cushing's syndrome. In embodiments, the disease isCushing's Disease.

Thus, in embodiments, the methods disclosed herein include a method fortreating a patient who is receiving ketoconazole treatment to reduce orblock the effects of steroids, said ketoconazole treatment comprisingadministering an original dose of ketoconazole to said patient, saidmethod comprising: administering a GRA to the patient receivingketoconazole, whereby the patient receiving ketoconazole is administereda GRA for treating the effects of steroids in the patient. Inembodiments, the GRA is mifepristone. In embodiments, the effects ofsteroids include hypercortisolemic effects, such as the effects ofCushing's syndrome. In embodiments, the effects of steroids includehormonal effects, such as effects on hormone-sensitive cancer.

Applicant further discloses a method for treating a Cushing's syndromepatient who is receiving ketoconzole treatment, said ketoconzoletreatment comprising administering an original dose of ketoconzole tosaid patient, said method comprising: administering a GRA to the patientreceiving ketoconzole, wherein the amount of GRA administered is a firstdose of GRA, whereby the patient receiving ketoconzole is administered aGRA for treating Cushing's syndrome. In embodiments, the GRA ismifepristone. In embodiments, the or Cushing's syndrome patient suffersfrom Cushing's Disease.

For example, the present disclosed methods include concomitantlyadministering to a patient in need thereof, a) an effective amount of aglucocorticoid receptor modulator (GRM), such as a glucocorticoidreceptor antagonist (GRA), and b) an effective amount of ketoconazole,such as ketoconazole, thereby reducing the effect, the amount, or both,of steroids such as cortisol in the patient. For example, a Cushing'ssyndrome patient may be in need of reducing their blood levels ofcortisol, or may be in need of reducing the effect of cortisol in thepatient. For example, a cancer patient may be in need of reducing theirblood levels of a steroid, such as an androgen, a progestogen, anestrogen, or other steroid.

Thus, in embodiments of the methods disclosed herein, a subjectcurrently receiving ketoconazole is administered a GRM. In embodimentsof the methods disclosed herein, a subject currently receivingketoconzole as treatment for a condition characterized by excess steroidlevels, or as treatment of a condition that is treated by reducingsteroid levels or by reducing steroid effects, is administered a GRM,whereby the subject is treated for that condition. In embodiments, thecondition is characterized by excessive cortisol levels. In embodiments,the condition is Cushing's syndrome. In embodiments, the condition is acancer characterized by the deleterious action of steroid hormones oncells, such as cancer cells; the cancer may be hormone-sensitive cancerthat may be treated by lowering the levels of a steroid in the patient.In embodiments, the hormone sensitive cancer is prostate cancer, breastcancer, or ovarian cancer.

Accordingly, Applicant discloses herein a method for treating a patientin need of reduced steroid levels, the patient receiving an originaldose of ketoconazole, said method comprising:

administering a first dose of a glucocorticoid receptor antagonist (GRA)to the patient, wherein said first GRA dose is administeredconcomitantly with said dose of ketoconazole, whereby the patient isadministered both an original dose of ketoconazole and a first dose of aGRA for reducing steroid levels in the patient. In embodiments of suchmethods, wherein said first dose of GRA comprises an amount of the GRAthat is effective to aid in reducing steroid levels in the patientwithout substantially increasing the level of ketoconazole in the bloodof the patient above that level produced by the original dose ofketoconazole, whereby the patient is administered both ketoconazole andan effective dose of a GRA and is not exposed to increased risk ofketoconazole toxicity.

Accordingly, Applicant discloses herein a method for treating a patientsuffering from excess steroid levels, the patient receiving an originaldose of ketoconazole, said method comprising:

administering a first dose of a glucocorticoid receptor antagonist (GRA)to the patient, wherein said first GRA dose is administeredconcomitantly with said dose of ketoconazole, whereby the patient isadministered both an original dose of ketoconazole and a first dose of aGRA for reducing steroid levels in the patient. In embodiments of suchmethods, wherein said first dose of GRA comprises an amount of the GRAthat is effective to aid in reducing steroid levels in the patientwithout substantially increasing the level of ketoconazole in the bloodof the patient above that level produced by the original dose ofketoconazole, whereby the patient is administered both ketoconazole andan effective dose of a GRA and is not exposed to increased risk ofketoconazole toxicity. In embodiments, the excess steroid comprisesexcess androgen. In embodiments, the excess steroid comprises excessprogestogen. In embodiments, the excess steroid comprises excessestrogen. In embodiments, the excess steroid comprises excess cortisol.

Accordingly, in further embodiments, Applicant discloses herein methodsfor treating a Cushing's syndrome patient, the patient receiving anoriginal dose of ketoconazole, said methods comprising:

administering a first dose of a glucocorticoid receptor antagonist (GRA)to the patient, wherein said first GRA dose is administeredconcomitantly with said dose of ketoconazole, whereby the patient isadministered both an original dose of ketoconazole and a first dose of aGRA for treating Cushing's syndrome. In embodiments of such methods,wherein said first dose of GRA comprises an amount of the GRA that iseffective to aid in the treatment of Cushing's syndrome withoutsubstantially increasing the level of ketoconazole in the blood of thepatient above that level produced by the original dose of ketoconazole,whereby the patient is administered both ketoconazole and an effectivedose of a GRA and is not exposed to increased risk of ketoconazoletoxicity.

In embodiments, Applicant discloses methods for treating a Cushing'ssyndrome patient who is receiving ketoconazole treatment, saidketoconazole treatment comprising administering an original dose ofketoconazole to said patient, said method comprising: administering saidoriginal dose of ketoconazole to said patient; and administering a firstdose of a glucocorticoid receptor antagonist (GRA) to the patient,wherein said first dose of GRA comprises an amount of said GRA that iseffective to aid in the treatment of Cushing's syndrome withoutsubstantially increasing the level of ketoconazole in the blood of thepatient above that level produced by the original dose of ketoconazole,whereby the patient is administered both ketoconazole and a GRA fortreating Cushing's syndrome and is not exposed to increased risk ofketoconazole toxicity. In embodiments, said GRA is mifepristone. Inembodiments, the original dose of ketoconazole and the first dose of GRAare administered within a short time of each other. In embodiments, theoriginal dose of ketoconazole and the first dose of GRA are administeredat substantially the same time. In embodiments, the original dose ofketoconazole and the first dose of GRA are administered concomitantly.In embodiments, the GRA is mifepristone.

Thus, in embodiments of these methods, administration of theketoconazole and of the GRA comprises concomitant administration of theoriginal dose of ketoconazole and the first dose of the GRA. Inembodiments of concomitant administration, ketoconazole and the GRA areadministered to the subject simultaneously. Such concomitantadministration of a GRA may be by oral administration; by intravenousadministration; subcutaneous administration; parenteral administration;intra-arterial administration; nasal administration; topicaladministration; or by other routes of administration, or combinationsthereof.

In embodiments of the methods disclosed herein, ketoconazole and the GRAare administered to the patient in a single pill containing both theketoconazole and the GRA, or are administered in a single liquidformulation containing both the ketoconazole and the GRA. Inembodiments, the GRA is mifepristone.

In embodiments of the methods disclosed herein, the first dose of theGRA is a dose selected from about 25 milligrams (mg), about 50 mg, about100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about600 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1500 mg, about1800 mg, and about 2000 mg. In embodiments, the dose of the GRA is adose of mifepristone selected from about 300 mg, about 600 mg, about 900mg, about 1200 mg, and about 1500 mg.

The methods disclosed herein include repeated administration of a GRA toa patient in need of treatment, including repeated concomitantadministration of ketoconazole and a GRA.

For example, in yet further embodiments, a second dose of GRA isadministered, wherein said second dose is administered after theadministration of the first dose of GRA. The second dose of GRA maycomprise about the same amount of said GRA as the first dose of the GRA;may comprise a greater amount of said GRA than the first dose of GRA; ormay comprise a smaller amount of GRA than the first dose of GRA. Inembodiments of these methods, the GRA is mifepristone.

The methods disclosed herein may further comprise: administering asubsequent dose of ketoconazole and a second dose of GRA, wherein saidsubsequent dose and said second dose are both administered after theadministration of the first dose of the GRA. In embodiments, the seconddose of GRA comprises about the same amount of the GRA as the first doseof GRA, and the subsequent dose of ketoconazole comprises about the sameamount of ketoconazole as the original dose of ketoconazole. Inembodiments, the subsequent dose of ketoconazole comprises a lesseramount of ketoconazole than the amount of the original dose ofketoconazole. In embodiments of these methods, the GRA is mifepristone.

In embodiments, the second dose of GRA comprises a greater amount of theGRA than the amount of said first dose of the GRA. In embodiments, thesecond dose of GRA comprises a greater amount of the GRA than the amountof said first dose of the GRA, and the subsequent dose of ketoconazolecomprises about the same amount of ketoconazole as the original dose ofketoconazole. In embodiments of these methods, the GRA is mifepristone.

In embodiments comprising repeated administration of a GRA to a patientin need of treatment, including repeated concomitant administration ofketoconazole and a GRA, ketoconazole and the GRA may be administeredsimultaneously. In embodiments of such methods, the GRA may bemifepristone.

In embodiments, ketoconazole and a GRA are administered to the patientin a single pill containing both ketoconazole and the GRA, or in asingle liquid formulation containing both ketoconazole and the GRA. Inembodiments, the (IRA is mifepristone.

Further embodiments of the methods disclosed herein may include furthersteps, e.g., may comprise administration of a third dose of a GRA,wherein said third dose of the GRA is administered after theadministration of the second dose of the GRA. In embodiments, such athird dose of GRA comprises about the same amount of the GRA as thesecond dose of the GRA. In embodiments, such a third dose of GRAcomprises a greater amount of the GRA than the second dose of the GRA.In embodiments, such a third dose of GRA is administered after theadministration of the second dose of the GRA. In embodiments, such athird dose of GRA comprises about the same amount of GRA as the amountof said second dose of the GRA. In embodiments, such a third dose of GRAcomprises a lesser amount of the GRA than the amount of said second doseof the GRA. In embodiments, such a third dose of GRA comprises a greateramount of the GRA than the amount of said second dose of the GRA. Insuch embodiments, the GRA may be mifepristone.

In embodiments, methods disclosed herein comprise concomitantadministration of ketoconazole and a third dose of GRA. In embodimentsof such concomitant administration, ketoconazole and the GRA areadministered to the patient simultaneously. In embodiments of suchconcomitant administration, ketoconazole and the GRA are administered tothe patient in a single pill containing both ketoconazole and the GRA,or in a single liquid formulation containing both ketoconazole and theGRA. In embodiments, the GRA is mifepristone.

Embodiments of the methods disclosed herein comprise treatments forpatients suffering from Cushing's syndrome; in embodiments, theCushing's syndrome patient suffers from Cushing's Disease. Suchtreatments for Cushing's syndrome comprise concomitant administration ofketoconazole and a GRA to the patient.

In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole treatment, the methods comprise concomitanttreatment of the patient with ketoconazole and with a glucocorticoidreceptor antagonist (GRA). In embodiments of methods of treating aCushing's syndrome patient who is receiving ketoconazole treatment, themethods comprise concomitant treatment of the patient with ketoconazoleand a GRA, wherein the dose of ketoconazole administered concomitantlywith the GRA is not reduced with respect to the ketoconazole doseadministered to the patient in the absence of concomitant treatment withketoconazole and a GRA. In embodiments of methods of treating aCushing's syndrome patient who is receiving ketoconazole treatment, themethods comprise concomitant treatment of the patient with a GRA andketoconazole. In embodiments, the GRA is mifepristone.

Applicant discloses herein methods for treating a Cushing's syndromepatient, the patient receiving an original dose of ketoconazole, saidmethod comprising: administering a first dose of a glucocorticoidreceptor antagonist (GRA) to the patient, wherein said first GRA dose isadministered concomitantly with the dose of SI, whereby the patient isadministered both an original dose of ketoconazole and a first dose of aGRA for treating Cushing's syndrome. In embodiments, the patient suffersfrom Cushing's Disease.

In embodiments, Applicant discloses herein methods for treating aCushing's syndrome patient, the patient receiving an original dose ofketoconazole, the method comprising: administering a first dose ofmifepristone to the patient, wherein the first mifepristone dose isadministered concomitantly with the dose of ketoconazole, whereby thepatient is administered both an original dose of ketoconazole and afirst dose of mifepristone for treating Cushing's syndrome. Inembodiments, the patient suffers from Cushing's Disease.

In further embodiments of such methods, wherein said first dose of a GRAcomprises a GRA amount that is effective to aid in the treatment ofCushing's syndrome without substantially increasing the level ofketoconazole in the blood of the patient above that level produced bysaid original dose of ketoconazole, whereby the patient is administeredboth ketoconazole and an effective dose of a GRA and is not exposed toincreased risk of ketoconazole toxicity. In embodiments, administrationof ketoconazole and of the GRA comprises concomitant administration ofthe original dose of ketoconazole and the first dose of the GRA. Inembodiments, administering a GRA comprises oral administration of theGRA. In embodiments, ketoconazole and the GRA are administered to thepatient simultaneously. In embodiments, ketoconazole and the GRA areadministered to the patient in a single pill containing bothketoconazole and the GRA, or in a single liquid formulation containingboth ketoconazole and the GRA. In embodiments, the GRA is mifepristone.

In embodiments of the methods disclosed herein, the first dose of theGRA is selected from about 25 mg, about 50 mg, about 100 mg, about 200mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 900mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1800 mg, about2000 mg, about 2100 mg, about 2400 mg, about 2700 mg, and about 3000 mg.In embodiments of the methods disclosed herein, the first dose of theGRA is a dose of mifepristone selected from about 1500 mg mifepristone,about 1200 mg mifepristone, about 900 mg mifepristone, about 600 mgmifepristone, and about 300 mg mifepristone.

Further embodiments of the methods disclosed herein compriseadministering a second dose of GRA, wherein said second dose isadministered after the administration of the first dose of GRA. Inembodiments, the second dose of GRA comprises about the same amount ofsaid GRA as the first dose of the GRA. In embodiments, the second doseof GRA comprises a greater amount of said GRA than the first dose ofGRA. In embodiments, the GRA is mifepristone.

Further embodiments of the methods disclosed herein compriseadministering a subsequent dose of ketoconazole and a second dose ofGRA, wherein the subsequent ketoconazole dose and the second GRA doseare both administered after the administration of the first dose of theGRA. In embodiments, the second dose of GRA comprises about the sameamount of the GRA as the first dose of the GRA, and the subsequent doseof ketoconazole comprises about the same amount of ketoconazole as theoriginal dose of ketoconazole. In embodiments, the subsequent dose ofketoconazole comprises a lesser amount of ketoconazole than the amountof the original dose of ketoconazole. In embodiments, the second dose ofGRA comprises a greater amount of the GRA than the amount of said firstdose of the GRA. In embodiments, the second dose of GRA comprises agreater amount of the GRA than the amount of the first dose of the GRA,and the subsequent dose of ketoconazole comprises about the same amountof ketoconazole as the original dose of ketoconazole. In embodiments,the GRA is mifepristone.

In embodiments, ketoconazole and the GRA are administered to the patientsimultaneously. In embodiments, the GRA is mifepristone. In embodiments,ketoconazole and the GRA are administered to the patient simultaneously.In embodiments, ketoconazole and mifepristone are administered to thepatient simultaneously. In embodiments, ketoconazole and the GRA areadministered to the patient in a single pill containing bothketoconazole and the GRA, or in a single liquid formulation containingboth ketoconazole and the GRA. In embodiments, ketoconazole andmifepristone are administered to the patient simultaneously. Inembodiments, ketoconazole and mifepristone are administered to thepatient in a single pill containing both ketoconazole and mifepristone,or in a single liquid formulation containing both ketoconazole andmifepristone. In embodiments, ketoconazole and mifepristone areadministered to the patient in a single pill comprising bothketoconazole and mifepristone, or in a single liquid formulationcomprising both ketoconazole and mifepristone.

Embodiments of the methods disclosed herein further compriseadministration of a third dose of GRA, wherein said third dose of theGRA is administered after the administration of the second dose of theGRA. In embodiments, the third dose of GRA comprises about the sameamount of the GRA as the second dose of the GRA. In embodiments, thethird dose of GRA comprises a greater amount of the GRA than the seconddose of the GRA. In embodiments, the methods further compriseadministration of a third dose of GRA, wherein the third dose of the GRAis administered after the administration of the second dose of the GRA.In embodiments, the third dose of GRA comprises about the same amount ofGRA as the amount of said second dose of the GRA. In embodiments, thethird dose of the GRA comprises a lesser amount of the GRA than theamount of said second dose of the GRA. In embodiments, the third dose ofGRA comprises a greater amount of the GRA than the amount of said seconddose of the GRA. In embodiments, administration of the third GRA dosecomprises concomitant administration ketoconazole and the third dose ofGRA. In such embodiments, ketoconazole and the GRA are administered tothe patient simultaneously. In embodiments of the methods comprisingsuch third dose of GRA, ketoconazole and the GRA are administered to thepatient in a single pill containing both ketoconazole and the GRA, or ina single liquid formulation containing both ketoconazole and the GRA. Inembodiments, the GRA is mifepristone.

Applicant discloses herein methods for treating Cushing's syndromepatients with a GRA (such as mifepristone) and ketoconazole. Inembodiments, the patient suffers from Cushing's Disease.

Applicant discloses here methods for treating a Cushing's syndromepatient who is receiving ketoconazole treatment, said ketoconazoletreatment comprising administering an original dose of ketoconazole tosaid patient, said method comprising: administering said original doseof ketoconazole to said patient; and administering a glucocorticoidreceptor antagonist (GRA) to the patient, wherein the amount of GRAadministered is a first dose of GRA, whereby the patient is administeredboth ketoconazole and a GRA for treating Cushing's syndrome. Inembodiments, the first dose of GRA is a lesser amount of GRA than wouldbe administered in the absence of ketoconazole. In embodiments, the GRAis mifepristone.

In embodiments of such methods of treating a Cushing's syndrome patientwho is receiving ketoconazole treatment, the first dose of GRA comprisesan amount of GRA that is effective to aid in the treatment of Cushing'ssyndrome without substantially increasing the level of ketoconazole inthe blood of the patient above that level produced by said original doseof ketoconazole, whereby the patient is administered both ketoconazoleand an effective dose of a GRA and is not exposed to increased risk ofketoconazole toxicity. In embodiments, the first dose of GRA is a lesseramount of GRA than would be administered in the absence of ketoconazole.In embodiments, the GRA is mifepristone.

In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole treatment, the administration of ketoconazoleand of the GRA comprises concomitant administration of the original doseof ketoconazole and the first dose of said GRA. In embodiments ofmethods of treating a Cushing's syndrome patient who is receivingketoconazole treatment, the administration of the GRA comprises oraladministration of the GRA. In embodiments of methods of treating aCushing's syndrome patient who is receiving ketoconazole treatment, theketoconazole and the GRA are administered to the patient simultaneously.In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole treatment, the ketoconazole and the GRA areadministered to the patient in a single pill containing bothketoconazole and the GRA. In embodiments of methods of treating aCushing's syndrome patient who is receiving ketoconazole treatment,ketoconazole and mifepristone are administered in a single liquidformulation comprising ketoconazole and mifepristone.

In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole treatment, the first dose of the GRA is a doseof GRA selected from about 25 mg, about 50 mg, about 100 mg, about 200mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 900mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1800 mg, about2000 mg, about 2100 mg, about 2400 mg, about 2700 mg, and about 3000 mg.In embodiments, the GRA is mifepristone, and the first dose of the GRAis a dose of mifepristone selected from about 1500 mg mifepristone,about 1200 mg mifepristone, about 900 mg mifepristone, about 600 mgmifepristone, and about 300 mg mifepristone.

In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole treatment, the methods further comprise:administering a second dose of GRA, wherein said second dose isadministered after the administration of the first dose of said GRA. Inembodiments of methods of treating a Cushing's syndrome patient who isreceiving ketoconazole treatment, the second dose of GRA comprises aboutthe same amount of said GRA as the first dose of the GRA. In embodimentsof methods of treating a Cushing's syndrome patient who is receivingketoconazole treatment, the second dose of GRA comprises a lesser amountof said GRA than the first dose of GRA. In embodiments, the second doseof GRA is a lesser amount of GRA than would be administered in theabsence of ketoconazole. In embodiments of methods of treating aCushing's syndrome patient who is receiving ketoconazole treatment, thesecond dose of GRA comprises a greater amount of said GRA than the firstdose of GRA. In embodiments, the GRA is mifepristone.

In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole treatment, the methods further comprise:administering a subsequent dose of ketoconazole and a second dose ofGRA, wherein the subsequent ketoconazole dose and the second GRA doseare both administered after the administration of the first dose of theGRA. In embodiments of methods of treating a Cushing's syndrome patientwho is receiving ketoconazole treatment, the second dose of the GRAcomprises about the same amount of the GRA as the first dose of the GRA,and the subsequent dose of ketoconazole comprises about the same amountof ketoconazole as the original dose of ketoconazole. In embodiments,the second dose of GRA is a lesser amount of GRA than would beadministered in the absence of ketoconazole.

In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole treatment, the subsequent dose of ketoconazolecomprises a lesser amount of ketoconazole than the amount of theoriginal dose of ketoconazole. In embodiments of methods of treating aCushing's syndrome patient who is receiving ketoconazole treatment, thesecond dose of the GRA comprises a greater amount of the GRA than theamount of said first dose of the GRA. In embodiments of methods oftreating a Cushing's syndrome patient who is receiving ketoconazoletreatment, the second dose of the GRA comprises a greater amount of theGRA than the amount of said first dose of the GRA, and said subsequentdose of ketoconazole comprises about the same amount of ketoconazole asthe original dose of ketoconazole. In embodiments of methods of treatinga Cushing's syndrome patient who is receiving ketoconazole treatment,the ketoconazole and the GRA are administered to the patientsimultaneously. In embodiments of methods of treating a Cushing'ssyndrome patient who is receiving ketoconazole treatment, theketoconazole and the GRA are administered to the patient in a singlepill containing both ketoconazole and the GRA, or in a single liquidformulation comprising ketoconazole and the GRA. In embodiments ofmethods of treating a Cushing's syndrome patient who is receivingketoconazole treatment, the GRA is mifepristone, and the ketoconazoleand the mifepristone are administered to the patient in a single pillcomprising both ketoconazole and mifepristone, or in a single liquidformulation comprising ketoconazole and mifepristone.

In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole treatment, the methods further comprise:administration of a third dose of the GRA, wherein the third dose of theGRA is administered after the administration of the second dose of theGRA. In embodiments, the third dose of GRA is a lesser amount of GRAthan would be administered in the absence of ketoconazole. In suchembodiments of methods of treating a Cushing's syndrome patient who isreceiving ketoconazole treatment, the third dose of GRA comprises aboutthe same amount of the GRA as the second dose of the GRA. In suchembodiments of methods of treating a Cushing's syndrome patient who isreceiving ketoconazole treatment, the third dose of the GRA comprises agreater amount of the GRA than the second dose of the GRA. In suchembodiments of methods of treating a Cushing's syndrome patient who isreceiving ketoconazole treatment, the third dose of the GRA isadministered after the administration of the second dose of the GRA. Insuch embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole treatment, the third dose of the GRA comprisesabout the same amount of GRA as the amount of said second dose of theGRA. In such embodiments of methods of treating a Cushing's syndromepatient who is receiving ketoconazole treatment, the third dose of theGRA comprises a lesser amount of the GRA than the amount of said seconddose of the GRA. In such embodiments of methods of treating a Cushing'ssyndrome patient who is receiving ketoconazole treatment, the third doseof the GRA comprises a greater amount of the GRA than the amount of saidsecond dose of the GRA. In embodiments, the GRA is mifepristone.

In such embodiments of methods of treating a Cushing's syndrome patientwho is receiving ketoconazole treatment, the methods compriseconcomitant administration of ketoconazole and of the third dose of theGRA. In embodiments of methods of treating a Cushing's syndrome patientwho is receiving ketoconazole treatment, the ketoconazole and the GRAare administered to the patient simultaneously. In embodiments ofmethods of treating a Cushing's syndrome patient who is receivingketoconazole treatment, the ketoconazole and the GRA are administered tothe patient in a single pill containing both ketoconazole and the GRA,or in a single liquid formulation comprising ketoconazole and the GRA.In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole treatment, the GRA is mifepristone, and theketoconazole and the mifepristone are administered to the patient in asingle pill comprising both ketoconazole and mifepristone, or in asingle liquid formulation comprising ketoconazole and mifepristone.

In embodiments of methods of treating a Cushing's syndrome patient whois receiving ketoconazole treatment, the methods comprise concomitanttreatment of the patient with mifepristone and ketoconazole. Inembodiments of methods of treating a Cushing's syndrome patient who isreceiving ketoconazole treatment, the methods comprise concomitanttreatment of the patient with mifepristone and ketoconazole, wherein thedose of ketoconazole administered concomitantly with ketoconazole is notreduced with respect to the ketoconazole dose administered to thepatient in the absence of concomitant treatment with ketoconazole andmifepristone.

Applicant discloses herein a method for treating a Cushing's syndromepatient who is receiving ketoconazole treatment, said ketoconazoletreatment comprising administering an original dose of ketoconazole tosaid patient, said method comprising: administering said original doseof ketoconazole to said patient; and administering mifepristone to thepatient, wherein the amount of mifepristone administered is a first doseof mifepristone, whereby the patient is administered both ketoconazoleand mifepristone for treating Cushing's syndrome. In embodiments, thefirst dose of mifepristone is a lesser amount of mifepristone than wouldbe administered in the absence of ketoconazole.

In embodiments of methods for treating a Cushing's syndrome patient whois receiving ketoconazole treatment, wherein the ketoconazole treatmentcomprises administering an original dose of ketoconazole to saidpatient, the methods comprise administering a first dose of mifepristonethat comprises an amount of mifepristone that is effective to aid in thetreatment of Cushing's syndrome without substantially increasing thelevel of ketoconazole in the blood of the patient above that levelproduced by said original dose of ketoconazole, whereby the patient isadministered both ketoconazole and an effective dose of mifepristone andis not exposed to increased risk of ketoconazole toxicity. Inembodiments of such methods, the administration of ketoconazole and ofmifepristone comprises concomitant administration of the original doseof ketoconazole and of the first dose of mifepristone. In embodiments ofsuch methods, the administration of mifepristone comprises oraladministration of mifepristone. In embodiments of such methods,ketoconazole and mifepristone are administered to the patientsimultaneously. In embodiments of such methods, ketoconazole andmifepristone are administered to the patient in a single pill comprisingboth ketoconazole and mifepristone, or in a single liquid formulationcomprising ketoconazole and mifepristone. In embodiments of suchmethods, the first dose of mifepristone is a dose of about 300milligrams (mg), about 600 mg, about 900 mg, about 1200 mg, or about1500 mg.

In embodiments, such methods further comprise: administering a seconddose of mifepristone, wherein said second dose is administered after theadministration of the first dose of mifepristone. In embodiments, thesecond dose of mifepristone is a lesser amount of mifepristone thanwould be administered in the absence of ketoconazole. In embodiments ofsuch methods, the second dose of mifepristone comprises about the sameamount of mifepristone as the first dose of mifepristone. In embodimentsof such methods, the second dose of mifepristone comprises a greateramount of mifepristone than the first dose of mifepristone. Inembodiments, such methods further comprise administering a subsequentdose of ketoconazole and a second dose of mifepristone, wherein saidsubsequent dose and said second dose are both administered after theadministration of the first dose of mifepristone. In embodiments of suchmethods, the second dose of mifepristone is a lesser amount ofmifepristone than would be administered in the absence of ketoconazole.In embodiments of such methods, the second dose of mifepristonecomprises about the same amount of mifepristone as the first dose ofmifepristone, and said subsequent dose of ketoconazole comprises aboutthe same amount of ketoconazole as the original dose of ketoconazole. Inembodiments of such methods, the subsequent dose of ketoconazolecomprises a lesser amount of ketoconazole than the amount of theoriginal dose of ketoconazole. In embodiments of such methods, thesecond dose of mifepristone comprises a greater amount of mifepristonethan the amount of said first dose of mifepristone. In embodiments ofsuch methods, the second dose of mifepristone comprises a greater amountof mifepristone than the amount of said first dose of mifepristone, andsaid subsequent dose of ketoconazole comprises about the same amount ofketoconazole as the original dose of ketoconazole. In embodiments ofsuch methods, ketoconazole and mifepristone are administered to thepatient simultaneously. In embodiments of such methods, ketoconazole andmifepristone are administered to the patient in a single pill comprisingboth ketoconazole and mifepristone, or in a single liquid formulationcomprising ketoconazole and mifepristone.

In embodiments, such methods further comprise administration of a thirddose of mifepristone, wherein said third dose of mifepristone isadministered after the administration of the second dose ofmifepristone. In embodiments, the third dose of mifepristone is a lesseramount of mifepristone than would be administered in the absence ofketoconazole. In embodiments of such methods, the third dose ofmifepristone comprises about the same amount of mifepristone as thesecond dose of mifepristone. In embodiments of such methods, the thirddose of mifepristone comprises a greater amount of mifepristone than thesecond dose of mifepristone. In embodiments, such methods furthercomprise administration of a third dose of mifepristone, wherein saidthird dose of mifepristone is administered after the administration ofthe second dose of mifepristone. In embodiments of such methods, thethird dose of mifepristone comprises about the same amount ofmifepristone as the amount of said second dose of mifepristone. Inembodiments of such methods, the third dose of mifepristone comprises alesser amount of mifepristone than the amount of said second dose ofmifepristone. In embodiments of such methods, the third dose ofmifepristone comprises a greater amount of mifepristone than the amountof said second dose of mifepristone. In embodiments, such methodscomprise concomitant administration of ketoconazole and of the thirddose of mifepristone. In embodiments of such methods, ketoconazole andmifepristone are administered to the patient simultaneously. Inembodiments of such methods, ketoconazole and mifepristone areadministered to the patient in a single pill comprising bothketoconazole and mifepristone, or in a single liquid formulationcomprising ketoconazole and mifepristone.

In embodiments of methods for treating a Cushing's syndrome patient whois receiving ketoconazole treatment at an original dose of ketoconazole,the methods comprise administering a first dose of mifepristone to thesubject and reducing the dose of ketoconazole received by the patient toa ketoconazole dose that is less than the original ketoconazole dose,wherein the dose of mifepristone comprises an amount of mifepristonethat is effective to aid in the treatment of Cushing's syndrome withoutsubstantially increasing the level of ketoconazole in the blood of thepatient above that level produced by said original dose of ketoconazole,whereby the patient is administered both ketoconazole and an effectivedose of mifepristone and is not exposed to increased risk ofketoconazole toxicity.

Accordingly, Applicant discloses herein a method for treating aCushing's syndrome patient who is receiving ketoconazole at an initialdosage, said initial dosage comprising administering an initial dose ofketoconazole to said patient, said method comprising: administering areduced dose of ketoconazole to said patient, wherein said reduced doseof ketoconazole is a dose of ketoconazole that is less than said initialdose by an amount of at least about 5% of the initial dose; andadministering mifepristone to the patient, wherein the amount ofmifepristone administered is a first dose of mifepristone, whereby thepatient is administered both the reduced dose of ketoconazole and thefirst dose of mifepristone. In embodiments of such methods, the firstdose of mifepristone comprises an amount of mifepristone that iseffective to aid in the treatment of Cushing's syndrome, whereby thepatient is administered both a reduced dose of ketoconazole and aneffective dose of mifepristone. In embodiments, the first dose ofmifepristone is a lesser amount of mifepristone than would beadministered in the absence of ketoconazole. In embodiments of suchmethods, the administration of ketoconazole and of mifepristonecomprises concomitant administration of the reduced dose of ketoconazoleand the first dose of mifepristone. In embodiments of such methods, theadministration of mifepristone comprises oral administration ofmifepristone. In embodiments of such methods, the first dose ofketoconazole is less than said initial dose of ketoconazole by an amountthat is about 10%, about 15%, about 25%, about 25%, about 30%, about35%, about 40%, about 45%, about 50%, about 60%, about 75%, or about 90%less than the initial dose. In embodiments of such methods, the firstdose of mifepristone is a dose selected from about 300 mg, about 600 mg,about 900 mg, about 1200 mg, and about 1500 mg.

In embodiments, such methods further comprise administering a seconddose of mifepristone, wherein said second dose is administered at a timeafter the administration of the first dose of mifepristone. Inembodiments, the second dose of mifepristone is a lesser amount ofmifepristone than would be administered in the absence of ketoconazole.In embodiments of such methods, the second dose of mifepri stonecomprises a lesser amount of mifepristone than the first dose ofmifepristone. In embodiments of such methods, the second dose ofmifepristone comprises about the same amount of mifepristone as thefirst dose of mifepristone. In embodiments of such methods, the seconddose of mifepristone comprises a greater amount of mifepristone than thefirst dose of mifepristone. In embodiments, such methods furthercomprise administering a subsequent dose of ketoconazole and a seconddose of mifepristone, wherein said subsequent dose and said second doseare both administered at a time after the administration of both thereduced dose of ketoconazole and of the first dose of mifepristone. Inembodiments of such methods, the second dose of mifepristone comprisesabout the same amount of mifepristone as the first dose of mifepristone,and said subsequent dose of ketoconazole comprises about the same amountof ketoconazole as the reduced dose of ketoconazole. In embodiments ofsuch methods, the subsequent dose of ketoconazole comprises a lesseramount of ketoconazole than the amount of said reduced dose ofketoconazole. In embodiments of such methods, the second dose ofmifepristone comprises a greater amount of mifepristone than the amountof said first dose of mifepristone. In embodiments of such methods, thesecond dose of mifepristone comprises a greater amount of mifepristonethan the amount of said first dose of mifepristone, and said subsequentdose of ketoconazole comprises about the same amount of ketoconazole asthe reduced dose of ketoconazole.

In embodiments, such methods further comprise administration of a thirddose of mifepristone, wherein said third dose of mifepristone isadministered at a time after the administration of the second dose ofmifepristone. In embodiments, the third dose of mifepristone is a lesseramount of mifepristone than would be administered in the absence ofketoconazole. In embodiments of such methods, the third dose ofmifepristone comprises a lesser amount of mifepristone than the seconddose of mifepristone. In embodiments of such methods, the third dose ofmifepristone comprises about the same amount of mifepristone as thesecond dose of mifepristone. In embodiments of such methods, the thirddose of mifepristone comprises a greater amount of mifepristone than thesecond dose of mifepristone.

In embodiments, such methods further comprise administration of a thirddose of mifepristone, wherein said third dose of mifepristone isadministered at a time after the administration of the second dose ofmifepristone. In embodiments, the third dose of mifepristone is a lesseramount of mifepristone than would be administered in the absence ofketoconazole. In embodiments of such methods, the third dose ofmifepristone comprises about the same amount of mifepristone as theamount of said second dose of mifepristone. In embodiments of suchmethods, the third dose of mifepristone comprises a lesser amount ofmifepristone than the amount of said second dose of mifepristone. Inembodiments of such methods, the third dose of mifepristone comprises agreater amount of mifepristone than the amount of said second dose ofmifepristone. In embodiments, such methods comprise administration of adose of ketoconazole administered at the time as the administration ofthe third dose of mifepristone.

Applicant further discloses herein methods for treating a patient who issuffering from Cushing's syndrome with mifepristone, the patient alsoreceiving concomitant administration of ketoconazole, said methodcomprising: to the patient concomitantly receiving ketoconazole, orallyadministering a dose of mifepristone that is a smaller dose ofmifepristone than the dose that is an effective mifepristone dose whenthe patient receives only mifepristone. An effective dose ofmifepristone when the patient receives only mifepristone for treatingCushing's syndrome is termed a “lone dose” of mifepristone. For example,the dose of mifepristone that is effective for the treatment of aCushing's syndrome patient not concomitantly receiving ketoconazole orother treatment for Cushing's syndrome is a “lone dose” of mifepristone.In embodiments of the methods disclosed herein, for Cushing's syndromepatient receiving concomitant administration of ketoconazole, the doseof mifepristone is reduced by at least about 5% as compared to the lonedose of mifepristone. Accordingly, Applicant discloses herein a methodfor treating a Cushing's syndrome patient who is receiving ketoconazole,said method comprising: administering a reduced dose of mifepristone tosaid patient, wherein said reduced dose of mifepristone is a dose ofmifepristone that is less than the lone dose of mifepristone as definedherein; whereby the patient is administered both ketoconazole and thereduced dose of mifepristone. In embodiments, such a reduced dose ofmifepristone is an amount of mifepristone that is less than the lonedose of mifepristone by an amount that is at least about 5% of the lonedose. In embodiments of such methods, the reduced dose of mifepristonecomprises an amount of mifepristone that is effective to aid in thetreatment of Cushing's syndrome, whereby the patient is administeredboth a reduced dose of mifepristone and a dose of ketoconazole. Inembodiments of such methods, the administration of ketoconazole and ofmifepristone comprises concomitant administration of the reduced dose ofmifepristone and the dose of ketoconazole. In embodiments of suchmethods, the administration of mifepristone comprises oraladministration of mifepristone. In embodiments of such methods, thereduced dose of mifepristone is less than said lone dose of mifepristoneby an amount that is about 10%, about 15%, about 25%, about 25%, about30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 75%,or about 90% less than the lone dose. In embodiments of such methods,the reduced dose of mifepristone is a daily dose selected from about 900mg, about 600 mg, about 300 mg, or is a dose of mifepristone selectedfrom about 300 mg mifepristone administered every other day, a dose ofabout 300 mg mifepristone administered every third day, and a dose ofmifepristone of about 300 mg administered every fourth day.

Compositions

Applicant discloses herein compositions comprising a glucocorticoidreceptor antagonist (GRA) which may be used in the treatment of apatient suffering from excess cortisol, e.g., in a patient sufferingfrom Cushing's syndrome. In embodiments, the compositions comprising aGRA may be provided in an amount effective to control hyperglycemiasecondary to hypercortisolism, and may be provided in an amounteffective control hyperglycemia secondary to hypercortisolism in apatient suffering from endogenous Cushing's disease. In embodiments, thecompositions comprising a GRA may be provided in an amount effective tocontrol hyperglycemia secondary to hypercortisolism in a patientsuffering from endogenous Cushing's disease, where the patient hasfailed surgery, or is not a candidate for surgery.

Applicant also discloses herein compositions comprising a glucocorticoidreceptor antagonist (GRA) and ketoconazole. These compositionscomprising a GRA and ketoconazole may be used in the treatment of aCushing's syndrome patient.

The compositions as disclosed herein can be prepared in a wide varietyof oral, parenteral and topical dosage forms. Oral preparations includetablets, pills, powder, dragees, capsules, liquids, lozenges, cachets,gels, syrups, slurries, suspensions, etc., suitable for ingestion by thepatient. The compositions of the present invention can also beadministered by injection, that is, intravenously, intramuscularly,intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.Also, the compositions disclosed herein can be administered byinhalation, for example, intranasally. Additionally, the compositions ofthe present invention can be administered transdermally. Thecompositions disclosed herein can also be administered by intraocular,intravaginal, and intrarectal routes including suppositories,insufflation, powders and aerosol formulations (for examples of steroidinhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa,Ann. Allergy Asthma Immunol. 75:107-111, 1995).

Accordingly, in embodiments disclosed herein, the compositions includepharmaceutical compositions including a pharmaceutically acceptablecarrier or excipient, a glucocorticoid receptor antagonist (GRA), and aSI. SIs include, for example, ketoconazole, levoketoconazole,metyrapone, aminoglutethimide, etomidate, LCI699 (Osilodrostat), andothers.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances, which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material. Details ontechniques for formulation and administration are well described in thescientific and patent literature, see, e.g., the latest edition ofRemington's Pharmaceutical Sciences, Mack Publishing Co, Easton Pa.(“Remington's”).

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from 5% or 10% to70% of ketoconazole and/or the GRA.

Suitable solid excipients include, but are not limited to, magnesiumcarbonate; magnesium stearate; talc; pectin; dextrin; starch;tragacanth; a low melting wax; cocoa butter; carbohydrates; sugarsincluding, but not limited to, lactose, sucrose, mannitol, or sorbitol,starch from corn, wheat, rice, potato, or other plants; cellulose suchas methyl cellulose, hydroxypropylmethyl-cellulose, or sodiumcarboxymethylcellulose; and gums including arabic and tragacanth; aswell as proteins including, but not limited to, gelatin and collagen. Ifdesired, disintegrating or solubilizing agents may be added, such as thecross-linked polyvinyl pyrrolidone, agar, alginic acid, or a saltthereof, such as sodium alginate.

Dragee cores are provided with suitable coatings such as concentratedsugar solutions, which may also contain gum arabic, talc,polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titaniumdioxide, lacquer solutions, and suitable organic solvents or solventmixtures. Dyestuffs or pigments may be added to the tablets or drageecoatings for product identification or to characterize the quantity ofactive compound (i.e., dosage). Pharmaceutical preparations of theinvention can also be used orally using, for example, push-fit capsulesmade of gelatin, as well as soft, sealed capsules made of gelatin and acoating such as glycerol or sorbitol. Push-fit capsules can containketoconazole and/or the GRA mixed with a filler or binders such aslactose or starches, lubricants such as talc or magnesium stearate, and,optionally, stabilizers. In soft capsules, ketoconazole and/or the GRAmay be dissolved or suspended in suitable liquids, such as fatty oils,liquid paraffin, or liquid polyethylene glycol with or withoutstabilizers.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and ketoconazoleand/or the GRA are dispersed homogeneously therein, as by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingketoconazole and/or the GRA in water and adding suitable colorants,flavors, stabilizers, and thickening agents as desired. Aqueoussuspensions suitable for oral use can be made by dispersing the finelydivided active component in water with viscous material, such as naturalor synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing orwetting agents such as a naturally occurring phosphatide (e.g.,lecithin), a condensation product of an alkylene oxide with a fatty acid(e.g., polyoxyethylene stearate), a condensation product of ethyleneoxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partialester derived from a fatty acid and a hexitol (e.g., polyoxyethylenesorbitol mono-oleate), or a condensation product of ethylene oxide witha partial ester derived from fatty acid and a hexitol anhydride (e.g.,polyoxyethylene sorbitan mono-oleate). The aqueous suspension can alsocontain one or more preservatives such as ethyl or n-propylp-hydroxybenzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose, aspartame orsaccharin. Formulations can be adjusted for osmolarity.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Oil suspensions can be formulated by suspending ketoconazole and/or theGRA in a vegetable oil, such as arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin; or a mixtureof these. The oil suspensions can contain a thickening agent, such asbeeswax, hard paraffin or cetyl alcohol. Sweetening agents can be addedto provide a palatable oral preparation, such as glycerol, sorbitol orsucrose. These formulations can be preserved by the addition of anantioxidant such as ascorbic acid. As an example of an injectable oilvehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. Thepharmaceutical formulations of the invention can also be in the form ofoil-in-water emulsions. The oily phase can be a vegetable oil or amineral oil, described above, or a mixture of these. Suitableemulsifying agents include naturally-occurring gums, such as gum acaciaand gum tragacanth, naturally occurring phosphatides, such as soybeanlecithin, esters or partial esters derived from fatty acids and hexitolanhydrides, such as sorbitan mono-oleate, and condensation products ofthese partial esters with ethylene oxide, such as polyoxyethylenesorbitan mono-oleate. The emulsion can also contain sweetening agentsand flavoring agents, as in the formulation of syrups and elixirs. Suchformulations can also contain a demulcent, a preservative, or a coloringagent.

The compositions of the present invention can also be delivered asmicrospheres for slow release in the body. For example, microspheres canbe formulated for administration via intradermal injection ofdrug-containing microspheres, which slowly release subcutaneously (seeRao, J. Biomater Sci. Polym. Ed, 7:623-645, 1995; as biodegradable andinjectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863,1995); or, as microspheres for oral administration (see, e.g., Eyles, J.Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermalroutes afford constant delivery for weeks or months.

In another embodiment, the compositions of the present invention can beformulated for parenteral administration, such as intravenous (IV)administration or administration into a body cavity or lumen of anorgan. The formulations for administration will commonly comprise asolution of the compositions of the present invention dissolved in apharmaceutically acceptable carrier. Among the acceptable vehicles andsolvents that can be employed are water and Ringer's solution, anisotonic sodium chloride. In addition, sterile fixed oils canconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil can be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid can likewisebe used in the preparation of injectables. These solutions are sterileand generally free of undesirable matter. These formulations may besterilized by conventional, well known sterilization techniques. Theformulations may contain pharmaceutically acceptable auxiliarysubstances as required to approximate physiological conditions such aspH adjusting and buffering agents, toxicity adjusting agents, e.g.,sodium acetate, sodium chloride, potassium chloride, calcium chloride,sodium lactate and the like. The concentration of the compositions ofthe present invention in these formulations can vary widely, and will beselected primarily based on fluid volumes, viscosities, body weight, andthe like, in accordance with the particular mode of administrationselected and the patient's needs. For IV administration, the formulationcan be a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension can be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents. The sterile injectable preparation canalso be a sterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, such as a solution of1,3-butanediol.

In another embodiment, the formulations of the compositions of thepresent invention can be delivered by the use of liposomes which fusewith the cellular membrane or are endocytosed, i.e., by employingligands attached to the liposome, or attached directly to theoligonucleotide, that bind to surface membrane protein receptors of thecell resulting in endocytosis. By using liposomes, particularly wherethe liposome surface carries ligands specific for target cells, or areotherwise preferentially directed to a specific organ, one can focus thedelivery of the compositions of the present invention into the targetcells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306,1996; Chonn, Curr Opin. Biotechnol, 6:698-708, 1995; Ostro, Am. J. Hosp.Pharm. 46:1576-1587, 1989).

Administration

The compositions disclosed herein can be delivered by any suitablemeans, including oral, parenteral and topical methods. Transdermaladministration methods, by a topical route, can be formulated asapplicator sticks, solutions, suspensions, emulsions, gels, creams,ointments, pastes, jellies, paints, powders, and aerosols.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the GRA and ketoconazole. In embodiments, theGRA is mifepristone. The unit dosage form can be a packaged preparation,the package containing discrete quantities of preparation, such aspicketed tablets, capsules, and powders in vials or ampoules. Also, theunit dosage form can be a capsule, tablet, cachet, or lozenge itself, orit can be the appropriate number of any of these in packaged form.

The GRA and ketoconazole can be co-administered or administeredseparately. Concomitant administration includes administeringketoconazole within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours ofthe GRA. Concomitant administration also includes administering the GRAand ketoconazole simultaneously, approximately simultaneously (e.g.,within about 1, 5, 10, 15, 20, or 30 minutes of each other), orsequentially in any order. Moreover, the GRA and ketoconazole can eachbe administered once a day, or two, three, or more times per day so asto provide the preferred dosage level per day. In embodiments, the GRAis mifepristone.

In some embodiments, concomitant administration can be accomplished byco-formulation, i.e., preparing a single pharmaceutical compositionincluding both the GRA and ketoconazole. Suitable co-formulationsinclude single pharmaceutical compositions including a GRA,ketoconazole, and a pharmaceutically acceptable excipient. Inembodiment, the GRA is mifepristone.

In other embodiments, the GRA and ketoconazole can be formulatedseparately.

Ketoconazole can be present in any suitable amount, and can depend onvarious factors including, but not limited to, weight and age of thesubject, state of the disease, etc. Suitable dosage ranges forketoconazole in combination with the GRA, include from about 0.1 mg toabout 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg to about750 mg, or about 25 mg to about 500 mg, or about 50 mg to about 250 mg.Suitable dosages for ketoconazole in combination with the GRA, includeabout 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400,500, 600, 700, 800, 900 or 1000 mg. In embodiments, the GRA ismifepristone.

Similarly, the GRA can be present in combination with ketoconazole inany suitable amount. The amount of GRA can depend on various factorsincluding, but not limited to, weight and age of the subject, state ofthe disease, etc. Suitable dosage ranges for the GRA in combination withthe SI, include from about 0.1 mg to about 10,000 mg, or about 1 mg toabout 1000 mg, or about 10 mg to about 750 mg, or about 25 mg to about500 mg, or about 50 mg to about 250 mg. Suitable dosages for the GRA incombination with ketoconazole, include, but are not limited to, about 1mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600,700, 800, 900 or about 1000 mg. In embodiments, the GRA is mifepristone,

Ketoconazole and the GRA can be present in the compositions of thepresent invention in any suitable weight ratio, such as from about 1:100to about 100:1 (w/w), or about 1:50 to about 50:1, or about 1:25 toabout 25:1, or about 1:10 to about 10:1, or about 1:5 to about 5:1(w/w). Ketoconazole and the GRA can be present in any suitable weightratio, such as about 1:100 (w/w), 1:50, 1:25, 1:10, 1:5, 1:4, 1:3, 1:2,1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 25:1, 50:1 or 100:1 (w/w). Other dosagesand dosage ratios of ketoconazole and the GRA are suitable in thecompositions and methods disclosed herein. In embodiments, the GRA ismifepristone.

The composition can also contain other compatible therapeutic agents.The compounds described herein can be used in combination with oneanother, or with adjunctive agents that may not be effective alone, butmay contribute to the efficacy of the active agent.

Kits

Applicant further provides kits including compositions as disclosedherein. Kits may also include instructions for the use of thecompositions.

In embodiments, a kit includes: a pharmaceutical composition containingketoconazole; and a pharmaceutical composition containing a GRA. Inembodiments, the GRA is mifepristone.

In embodiments, a kit includes: a pharmaceutical composition containingketoconazole; and a pharmaceutical composition containing a GRA; andinstructions for the use (e.g., administration) of the ketoconazole andthe GRA. In embodiments, the GRA is mifepristone, and the instructionsinclude instructions for the administration of mifepristone. Inembodiments, the instructions include instructions regarding one or moreof the number of pharmaceutical compositions to be taken each day, thetiming of such administration, whether or not the pharmaceuticals are tobe taken with food or in a fasted state, contraindications, possibleside effects, activities to be avoided during treatment with thepharmaceutical compositions (if any), and foods to be avoided duringtreatment with the pharmaceutical compositions (if any).

In embodiments, a kit includes: a pharmaceutical composition containingketoconazole and a GRA. In embodiments, the GRA is mifepristone, and thepharmaceutical composition contains ketoconazole and mifepristone.

In embodiments, a kit includes: a pharmaceutical composition containingketoconazole and a GRA; and instructions for the use (e.g.,administration) of the pharmaceutical composition. In embodiments, theGRA is mifepristone. In embodiments of the kits disclosed herein, thepharmaceutical composition includes ketoconazole and mifepristone, andthe instructions include instructions for the administration of thepharmaceutical containing ketoconazole and mifepristone. In embodiments,the instructions include instructions regarding one or more of thenumber of pharmaceutical compositions to be taken each day, the timingof such administration, whether or not the pharmaceutical composition isto be taken with food or in a fasted state, contraindications, possibleside effects, activities to be avoided during treatment with thepharmaceutical composition (if any), and foods to be avoided duringtreatment with the pharmaceutical composition (if any).

EXAMPLES

The following examples are presented by way of illustration ofembodiments of the methods disclosed herein, and serve to illustrate,but not to limit, the present disclosure of methods of treating patientssuffering from Cushing's syndrome, including Cushing's Disease; or fromprostate cancer and other androgen-sensitive cancers; or from breastcancer, ovarian cancer, or other cancer hormone-sensitive cancer (e.g.,cancer sensitive to estrogen or progesterone); and patients sufferingfrom other diseases, disorders, or syndromes.

Example 1

A study was performed in order to determine the effect of oralketoconazole at a dose of 400 mg once per day (OD) or 200 mg twice perday (BID) on the plasma pharmacokinetics of a 300 mg single dose ofmifepristone given to a fasted subject, in comparison to previous studydata. This study was an open-label study in healthy male subjects.

Healthy male volunteers between the ages of 18 to 45 years of age with abody mass index (BMI) ranging between 19 and 32 kg/m2 and a weight of atleast 60 kg (132 lbs) were enrolled. Subjects had no clinicallysignificant abnormal findings on the physical examination, ECG, bloodpressure, heart rate, medical history, or clinical laboratory resultsduring screening. The QTc interval at screening was less than 450 msec.

In cohort 1, six subjects received ketoconazole 400 mg OD for 14 days.The cohort 1 subjects participated in a screening visit to assesseligibility, and in a check-in day during which eligibility wasre-confirmed and the first dose of 400 mg oral ketoconazole given atapproximately 8 PM (12 hours prior to expected time of Day 1mifepristone dose).

The morning of Day 1, subjects received 400 mg oral ketoconazole fasted,0.5 hour prior to receiving the 300 mg single dose of mifepristonefasted. Subjects remained in the clinic on Days 2 and 3 to receive 400mg OD oral ketoconazole fasted, and for safety evaluation and collectionof blood pharmacokinetic (PK) samples. Subjects were discharged from theclinic on Day 4 following administration of 400 mg OD oral ketoconazolefasted, and returned to the clinic the mornings of Days 5 through 13 toreceive 400 mg OD oral ketoconazole fasted.

In cohort 2, six subjects received ketoconazole 200 mg BID for 14 days.The 300 mg single dose of mifepristone was given to all subjects onday 1. All 12 subjects completed the study. Cohort 2 subjectsparticipated in a Screening visit to assess eligibility and a check-inDay (Day −1) during which eligibility was re-confirmed. On Day 0,subjects received 200 mg BID oral ketoconazole: the morning dose afteran overnight fast and the evening dose 12 hours prior to expected timeof Day 1 Mifepristone dose. The morning of Day 1, subjects received 200mg oral ketoconazole fasted, 0.5 hour prior to receiving the 300 mgsingle dose of Mifepristone fasted. The evening of Day 1, subjectsreceived 200 mg oral ketoconazole. Subjects remained in the clinic onDays 2, 3 and 4 to receive 200 mg BID oral ketoconazole, and for safetyevaluation and collection of blood pharmacokinetic (PK) samples.Subjects were discharged from the clinic on Day 4 following eveningadministration of 200 mg oral ketoconazole, and returned to the clinicthe morning and evening of Days 5 through 13 to receive 200 mg BID oralketoconazole. Morning doses of ketoconazole on Days 0-13 wereadministered in the fasted state.

Subjects in both cohorts had blood sampling for determination of plasmaconcentrations of mifepristone and its metabolites within 30 minutesbefore mifepristone dosing and at hours 0.5, 1, 2, 4, 6, 8, 12, 24, 36,48, 60, 72 (Day 4), 120 (Day 6), 192 (Day 9), 264 (Day 12), and 336 (Day15) post mifepristone dose. Subjects in both cohorts returned to thestudy center on Day 15 for safety monitoring, and completion of theTermination Visit procedures, followed by discharge from the study.Safety was assessed by spontaneously reported adverse events, physicalexaminations, and routine clinical laboratory tests. To the extentpossible, any adverse events deemed study drug-related and that wereongoing at the time of discharge from the study were followed-up toresolution or until a determination is made that the unresolved eventwas stable.

No subject experienced a serious adverse effect (SAE), or an adverseevent (AE) that resulted in discontinuation from the study. Threesubjects (25%) experienced at least 1 treatment-emergent adverse event(TEAE). All TEAEs were mild in intensity. No TEAE was considered by theinvestigator to be related to mifepristone. One TEAE of insomnia wasconsidered by the investigator to be related to ketoconazole.

Minimal changes in laboratory test results were observed during thecourse of the study. No laboratory test result was considered by theinvestigator to be a TEAE. Any abnormal values or shifts from baselinewere considered not clinically significant. No clinically significantchanges in any electrocardiogram (ECG) parameter were observed.

Pharmacokinetics (PK): Blood samples were drawn within 30 minutes beforemifepristone dosing and at hours 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 60,72 (Day 4), 120 (Day 6), 192 (Day 9), 264 (Day 12), and 336 (Day 15)post mifepristone dose. Pharmacokinetic parameters were calculated forplasma concentrations of mifepristone and its metabolites following thesingle dose at Day 1. Descriptive statistics (count, mean, median,standard deviation, minimum, maximum, and % coefficient of variation)were provided. Mifepristone/metabolite concentrations were listed andsummarized. Comparisons with previous study data were made. The mean PKparameters from this study are presented in Table 1 (“MIFE” indicatesmifepristone). The abbreviations and symbols used in Table 1 have thefollowing meanings: “Tmax” indicates time to maximum observed plasmaconcentration; “Tmin” indicates time to minimum observed concentrationwithin the 24 hour dosing interval; “Cmax” indicates maximum observedplasma concentration; “Cmin” indicates minimum observed concentrationwithin the 24 hour dosing interval; “Cavg” indicates averagesteady-state concentration and is defined as drug input rate (Ro)divided by drug removal rate (CLss) (Cavg=Ro/CLss, where f (the fractionabsorbed) cancels out (f is a factor of both Ro and CLss); this equationreduces to Cavg=AUCtau/tau); “AUC0-24” indicates area under the plasmaconcentration versus time curve from time 0 to 24 hours post-dose,calculated using the linear trapezoidal rule (this is the same as AUCtauwhere tau is 24 hours or 1 day); “% Fluct” indicates percent fluctuationin drug concentrations at steady-state computed as %Fluct=100×(Cmax−Cmin)/Cavg.

PHARMACOKINETIC (PK) RESULTS: Mifepristone plasma concentrations showeda rapid initial decline followed by a slow decline over time. At latertime points, concentrations showed an accelerated decline indicative ofnon-linear kinetics. Metabolites peaked later relative to parentmifepristone as would be expected. Mifepristone metabolite RU 42633exposure was similar or even greater than that for mifepristone, whileRU 42698 (a mifepristone metabolite) exposure was approximately 0.74 to0.94 relative to mifepristone and RU 42848 (also a mifepristonemetabolite) exposure was 0.53 to 0.68 relative to mifepristone. Withincrease in time interval, the fraction of AUC relative to mifepristoneaccounted for by metabolite increased.

Cohort 2 Cmax (where Cmax is the maximum observed plasma concentration)and AUCinf (where AUCinf is the area under the concentration-time curvefrom time of last dose to infinity) were similar to correspondingparameters in Cohort 1. The geometric mean ratio (GMR) for Cmax was 1.15and that for AUCinf was 1.05. However, the 90% confidence intervalsaround the GMR were higher than the standard 80:125 reference interval.Thus, there may be a small increase in mifepristone exposure with adivided ketoconazole dose (200 mg BID vs. 400 mg OD), but this wasminor. Terminal half-life was approximately the same in Cohort 2 versusCohort I and Tmax was shorter for Cohort 2 versus Cohort I.

SAFETY RESULTS: Among 12 subjects who received mifepristone, 3 (25%)experienced at least one treatment emergent adverse event (TEAE). AllTEAEs were mild in intensity. No TEAE was considered by the investigatorto be related to Mifepristone. One TEAE of insomnia was considered bythe investigator to be related to ketoconazole. No subject experiencedan SAE or an AE that resulted in discontinuation from the study. Minimalchanges in laboratory test results were observed for subjects during thecourse of the study. No laboratory test result was considered by theinvestigator to be a TEAE. Any abnormal values or shifts from Baselinevalues were considered not clinically significant. No clinicallysignificant changes in any ECG parameter were observed.

While PK parameters in Cohort 2 were similar to those in Cohort I, the90% confidence intervals around the GMR were higher than the standard80:125 reference interval used for bioequivalence testing. Thus, theremay be a small and minor increase in mifepristone exposure with adivided ketoconazole dose (200 mg BID vs. 400 mg OD). Terminal half-lifewas approximately the same in Cohort 2 versus Cohort 1 and Tmax wasshorter for Cohort 2 versus Cohort 1. Mifepristone 300 mg was safe andwell tolerated in healthy volunteers under the following treatmentregimens: single-dose fasted with ketoconazole 400 mg OD for 14 days orketoconazole 200 mg BID for 14 days.

Example 2

The primary objective of this study was to determine the effect of a 400mg single dose of ketoconazole on the PK of an 8-day regimen of 300 mgor 600 mg OD mifepristone given following a moderate fat (34%)breakfast. This was an open-label study in healthy male subjects. Incohort 1, six subjects received mifepristone 300 mg OD for 8 days. Incohort 2, six subjects received mifepristone 600 mg OD for 8 days. The400 mg single dose of ketoconazole was given to all subjects on day 8.Three subjects discontinued early from the study: one subject in cohort1 due to new onset sinus bradycardia, and two subjects in cohort 2 dueto withdrawn consent.

METHODOLOGY: Twelve subjects were enrolled, six in Cohort 1 and 6 inCohort 2. Three subjects discontinued early from the study, one subjectin Cohort 1 due to an adverse event of sinus bradycardia, and twosubjects in Cohort 2 due to withdrawn consent.

Cohort 1: Subjects participated in a Screening visit to assesseligibility, and returned to the clinic on Days 1-6 to receive 300 mgoral mifepristone following a moderate fat breakfast. On Day 7 subjectswere admitted to the clinic in the fasted state for a pre-dose PK blooddraw, after which they received 300 mg oral mifepristone following amoderate fat breakfast. Subjects had serial blood sampling fordetermination of mifepristone and its metabolites at hours 0.5, 1, 2, 4,6, 8, and 12 post Day 7 dose. On Day 8, a pre-dose PK sample was drawnwithin 30 minutes prior to ketoconazole dosing for determination ofplasma concentrations of mifepristone and its metabolites andketoconazole. Following a moderate fat breakfast on Day 8, subjectsreceived 400 mg ketoconazole 0.5 hours prior to 300 mg mifepristone andhad serial blood sampling at hours 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48,60, 72, and 120 post mifepristone dose for determination of plasmaconcentrations of mifepristone and its metabolites; and at hours 0.5, 1,1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 post ketoconazole dose fordetermination of plasma concentrations of ketoconazole. Subjects weredischarged on Day 11.

Cohort 2: Subjects participated in a Screening visit to assesseligibility and returned to the clinic on Days 1-6 to receive 600 mgoral mifepristone following a moderate fat breakfast. On Day 7 subjectswere admitted to the clinic in the fasted state for a pre-dose PK blooddraw, after which they received 600 mg oral mifepristone following amoderate fat breakfast. Subjects had serial blood sampling fordetermination of mifepristone and its metabolites at hours 0.5, 1, 2, 4,6, 8, and 12 post Day 7 dose. On Day 8, a pre-dose PK sample was drawnwithin 30 minutes prior to ketoconazole dosing for determination ofplasma concentrations of mifepristone and its metabolites andketoconazole. Following a moderate fat breakfast on Day 8, subjectsreceived 400 mg ketoconazole 0.5 hours prior to 600 mg mifepristone andhad serial blood sampling at hours 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48,60, 72, and 120 post mifepristone dose for determination of plasmaconcentrations of mifepristone and its metabolites; and at hours 0.5, 1,1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 post ketoconazole dose fordetermination of plasma concentrations of ketoconazole. Subjects weredischarged on Day 11. Subjects in both cohorts returned to study centeron Day 13 for safety monitoring, collection of the 120-hour PK draw, andcompletion of the Termination Visit procedures, followed by dischargefrom the study. To the extent possible, any adverse events deemed studydrug-related and that were ongoing at the time of discharge from thestudy were followed-up to resolution or until a determination was madethat the unresolved event was stable.

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: Healthy male volunteersbetween the ages of 18 to 45 years of age with a body mass index (BMI)ranging between 19 and 32 kg/m2 and a weight of at least 60 kg (132 lbs)were enrolled. Subjects had no clinically significant abnormal findingson the physical examination, ECG, blood pressure, heart rate, medicalhistory, or clinical laboratory results during screening. The QTcinterval at screening was less than 450 msec.

DURATION OF TREATMENT: Up to a total of 28 days, including up to 2 weeksscreening, dosing on Days 1-8, safety observation, and PK samplecollection through Day 13. For measuring the pharmacokinetics ofmifepristone, samples were collected within 30 minutes before Day 7mifepristone dose and at hours 0.5, 1, 2, 4, 6, 8, and 12 post Day 7mifepristone dose; within 30 minutes before Day 8 ketoconazole dosingand at hours 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, and 120 postDay 8 mifepristone dose. For measuring the pharmacokinetics ofketoconazole, samples were collected predose on Day 8 (24 hr sample fromDay 7), and at hours 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48hours post ketoconazole dose.

Safety was assessed by spontaneously reported adverse events, physicalexaminations, and routine clinical laboratory tests. Adverse event datawere tabulated. Physical findings and laboratory test results werelisted by subject.

SAFETY RESULTS: No subject experienced an SAE. Among twelve subjects whoreceived mifepristone, six subjects (50%) experienced at least 1 TEAE.TEAEs were predominantly mild in intensity. The majority of subjects(5/6) with TEAEs were in Cohort 2 and onset of the majority of TEAEsoccurred on or after Day 8 during treatment with both ketoconazole andmifepristone 600 mg. TEAEs considered possibly or probably related tomifepristone administration in four subjects in Cohort 2 were dizziness,nausea, vomiting, dry mouth, and rash. One TEAE of headache wasconsidered by the investigator to be possibly related to bothketoconazole and mifepristone administration. One subject in Cohort 1with a TEAE of nodal arrhythmia on Day 8 was withdrawn by theinvestigator. The event was considered mild in severity and notconsidered related to study medication. The corresponding ECGabnormality noted as “sinus bradycardia” was considered not clinicallysignificant. No subject experienced an SAE.

Minimal changes in laboratory test results were observed for subjectsduring the course of the study. No laboratory test result was consideredby the investigator to be a TEAE. There were no clinically significantchanges or abnormalities in vital signs, physical examinations or bodyweights during the study. Abnormal ECGs occurred in four subjects and noabnormality was considered clinically significant.

STATISTICAL METHODS: Pharmacokinetics (PK): Pharmacokinetic parametersCmax, Ctrough, and interdosing interval AUC were calculated for plasmaconcentrations of mifepristone and its metabolites following dose onDays 7 and 8. Descriptive statistics (count, mean, median, standarddeviation, minimum, maximum, and % coefficient of variation) wereprovided. mifepristone/metabolite concentrations were listed andsummarize. GM means of Cmax and AUC0-24 were compared for Day 8 to Day 7in this study and also to combined data of 300 mg OD mifepristone inprevious multiple dose studies. Additionally, comparisons were madebetween the PK results of cohort 1 and 2 Pharmacokinetic parametersCmax, T1/2 and total AUC were calculated for plasma concentrations ofketoconazole following the single dose on Day 8. Descriptive statisticscount, mean, median, standard deviation, minimum, maximum, and %coefficient of variation) were provided. Ketoconazole concentrationswere listed and summarized. GM means of Cmax and total AUC were comparedfor the single dose in this study to the combined data of reported 400mg single doses of ketoconazole of healthy subjects from the literature.

The mean (±SD) age of subjects was 29.4±6.8 years, and the mean BMI atscreening was 25.61±3.27 kg/m2. Seven of twelve subjects (58.3%) wereWhite, and 5/12 (41.7%) were Black/African American. Five of the 12subjects (41.7%) were of Hispanic or Latino ethnicity.

PHARMACOKINETIC (PK) RESULTS: PK data for mifepristone and metaboliteswas available for eleven of the 12 enrolled subjects and data forketoconazole PK analyses was available for 10 subjects. Concentrationsof mifepristone and each metabolite were above the limits of detectionduring the entire sampling duration from Day 7 predose to Day 13 (end ofstudy). mifepristone plasma concentrations showed a rapid initialdecline followed by a slow decline over time and metabolites peakedlater relative to parent mifepristone as expected. Mean RU 42633 and RU42848 exposure was similar or even greater than that for mifepristone,while RU 42698 exposure was lower. Ketoconazole PK after a single doseon Day 8 was readily computed. Co-administration of ketoconazoleincreased mifepristone and metabolite exposure. In the presence of 400mg ketoconazole on Day 8, Cohort 1 mifepristone Cmax and AUC0-24increased by 20% and 25% relative to the prior Day 7 withoutketoconazole. This effect was slightly greater at 600 mg OD mifepristonein Cohort 2, where Cmax and AUC0-24 increased by 39% and 28% between Day7 and Day 8. A dose of 600 mg OD mifepristone (Cohort 2) resulted inhigher mifepristone and metabolite exposure relative to a dose of 300 mgOD (Cohort 1) both alone and in the presence of 400 mg ketoconazole.This increase was less than proportionate to the two-fold doseincrement. On Day 7 without ketoconazole, mifepristone Cmax and AUC0-24at 600 mg OD were 42% and 48% greater than at 300 mg OD. This doseeffect was greater in the presence of 400 mg ketoconazole. Day 8mifepristone Cmax and AUCO-24 were 65% and 52% greater at 600 mg OD thanat 300 mg OD. mifepristone half-life on Day 8 in the presence of 400 mgketoconazole was similar between the two mifepristone dose levels. Day 8half-life was 13% greater at 600 mg OD than at 300 mg OD. Ketoconazoleexposure following a single 400 mg dose on Day 8 of a regimen of 600 mgOD mifepristone was 37% and 36% higher (Cmax and AUCinf) relative to amifepri stone regimen of 300 mg OD. Ketoconazole half-life on eithermifepristone regimen was not appreciably different. The addition of asingle dose of 400 mg ketoconazole to 300 mg or 600 mg OD mifepristoneon Day 8 resulted in exposure increases in Cmax and AUC0-24 that weresimilar to historical values at 600 mg or 1200 mg OD in the fasted stateand 1200 mg OD in the fed state, respectively. Although the increase inexposure due to the addition of ketoconazole was only between 20% and39% in absolute terms, the resulting exposure was similar to that of adose 2 to 3 times greater. This is believed to be due to a lack ofdose-proportional kinetics for mifepristone.

The mean PK parameters and results from this study are presented inTable 2.

The abbreviations and symbols used in Table 2 have the followingmeanings:

“Tmax” indicates time to maximum observed plasma concentration; “Tmin”indicates time to minimum observed concentration within the 24 hourdosing interval; “Cmax” indicates maximum observed plasma concentration;“Cmin” indicates minimum observed concentration within the 24 hourdosing interval; “Cavg” indicates average steady-state concentration andis defined as drug input rate (Ro) divided by drug removal rate (CLss)(Cavg=Ro/CLss, where f cancels out; this equation reduces toCavg=AUCtau/tau); “AUC0-24” indicates area under the plasmaconcentration versus time curve from time 0 to 24 hours post-dose,calculated using the linear trapezoidal rule (this is the same as AUCtauwhere tau is 24 hours or 1 day); “% Fluct” indicates percent fluctuationin drug concentrations at steady-state computed as %Fluct=100×(Cmax−Cmin)/Cavg.

Drug-drug interaction (DDI) effects of ketoconazole on mifepristone andof mifepristone on ketoconazole were studied. A single 400 ma dose ofketoconazole caused a detectable increase in mifepristone exposure atmifepristone doses of 300 and 600 mg OD, and mifepristone at these dosescaused a detectable increase in ketoconazole exposure. Although theincrease in mifepristone exposure due to the addition of ketoconazolewas only between 20% and 39% in absolute terms, the resulting exposurewas similar to that of a dose 2 to 3 times greater. This is believed tobe due to a lack of dose-proportional kinetics for mifepristone.Predominantly mild AEs occurred and were observed primarily in subjectsadministered ketoconazole and mifepristone 600 mg.

Example 3

A Phase 1, single-center, open-label study was performed to study theeffect of oral twice-daily doses of 200 mg of ketoconazole given withmultiple oral once-daily doses of 600 mg of mifepristone in healthy malevolunteers, during which all drug administrations were given after atypical meal (34% fat content). An objective of this study was todetermine the effect of ketoconazole 200 mg twice daily on the PK ofmifepristone 600 mg once daily when both drugs were administered withfood. A single dose of ketoconazole was administered on Day −1. Duringmultidose administration, mifepristone was administered on Days 1-17 andketoconazole on Days 13-17; follow-up continued on Days 18-31. Sixteensubjects were enrolled (mean age 31.9 years; 8 black. 6 white, 2 other),and two subjects discontinued before starting themifepristone/ketoconazole combination treatment.

The study was a two period study design. In Period 1: 600 mgmifepristone was administered once daily from Day 1 to Day 12;pharmacokinetic samples were taken before each dose for assay ofmifepristone and active metabolites (mono-demethylated metabolite, RU42633; hydroxylated metabolite, RU 42698; and di-demethylatedmetabolite, RU 42848) to confirm that steady-state was achieved, and fora dose-interval concentration-profile on Day 12. In Period 2: 600 mgmifepristone once daily was continued in combination with 200 mgketoconazole twice daily from Days 13 to 17; pharmacokinetic sampleswere taken for assay of both mifepristone and metabolites, andketoconazole before dosing on Days 13 to 17, and on Day 17 for adose-interval concentration-time profile

A secondary objective was to determine if the effect of 200 mg BIDketoconazole on the PK of co-administered 600 mg OD mifepristone atsteady-state exceeded exposure to mifepristone and metabolites comparedto that of 1200 mg OD mifepristone with food, the labeled dosing regimenwith the highest mean observed exposure in healthy subjects.

Effects of Co-Administration with Ketoconazole on Mifepristone andMetabolites: The concentrations of mifepristone and the hydroxylatedmetabolite, RU 42698, were higher on Day 17 (600 mg mifepristone dailyco-administered with 200 mg ketoconazole twice daily) than on Day 12(mifepristone alone). Concentrations of RU 42633 and RU 42848 weresimilar on Day 17 and Day 12. Results of the formal statistical analysisare shown in Table 3.

For mifepristone, the geometric mean ratio of test to reference forC_(max) was 127.59% (90% CI: 116.66, 139.54, where “CI” means“confidence interval” and “90% CI” means “90% confidence interval”) andfor AUC₀₋₂₄ was 138.01% (90% CI: 127.12, 149.84). The lower bound of the90% confidence intervals exceeded 100% and the upper bound exceeded125%. Thus, co-administration with ketoconazole increased mifepristoneexposure. Similarly, for metabolite RU 42698, the lower bounds of the90% confidence intervals exceeded 100% and both geometric mean ratiosand the upper bound of the 90% confidence interval exceeded 125%, andthus exposure to this metabolite was increased by ketoconazole.

For metabolites RU 42848 and RU 42633, the calculated geometric meanratios and 90% confidence intervals of exposure ratios were within thestandard 80:125 comparison interval and thus not affected byketoconazole.

Effects of Co-administration with mifepristone on Ketoconazole: Theplasma concentration-time profiles of ketoconazole given twice dailywith mifepristone on Day 17 were much higher than for ketoconazole givenas a single dose alone on Day −1. Results of the formal statisticalanalysis are shown in Table 4.

The geometric mean ratio of test to reference for C_(max) was 252.71%(90% CI: 214.85, 297.26) and for AUC was 365.36% (90% CI: 333.78,399.93). Thus, the geometric mean ratio and both lower and upper boundsof the 90% confidence intervals were entirely above the standard 80:125comparison interval and exposure on Day 17 (with mifepristone) washigher than on Day −1 (ketoconazole alone).

Comparison of Mifepristone Exposure with mifepristone Labeled Doses: Theconcentration-time plots showed that mean mifepristone concentrations onDay 17 in the present study were less than those in the fed condition ina previous “historic” study in which subjects received 1200 mgmifepristone daily for seven days. Mifepristone was administered to thesubjects within thirty minutes following a typical meal (34% fat) inboth the present study and in the historic study. Results of the formalstatistical analysis are shown in Table 5.

For mifepristone, the geometric mean ratio of test to reference forC_(max) was 84.64% (90% CI: 72.92, 98.23); for AUC₀₋₂₄ it was 87.27%(90% CI: 74.72, 101.94). The 90% confidence intervals were below andoverlapping the standard 80:125 comparison interval. The meanmifepristone concentrations in subject receiving 600 mg mifepristonefollowing a 34% fat meal were less than the mifepristone concentrationsin the historic study. As shown in Table 5, administration of 600 mgmifepristone in the fed state with ketoconazole resulted in mifepristoneconcentrations that were less than the mifepristone concentrationsmeasured in subjects receiving 1200 mg mifepristone daily in the absenceof ketoconazole. The Geometric Mean Ratio (GMR) values in Table 5suggest that mifepristone 600 mg co-administered with ketoconazoleyields mifepristone exposure 13-15% less than that of 1200 mgmifepristone in the absence of ketoconazole; for the metabolites,corresponding values range from an 18-19% decrease to a 17-18% increase.Thus, administration of 600 mg mifepristone daily with ketoconazoleresulted in mifepristone concentrations that were not higher than themean observed exposure at 1200 mg mifepristone; both treatments givenfollowing typical 34% fat meal. The value of 87% for GMR of the AUCssuggests that 900 mg mifepristone in the presence of ketoconazole wouldbetter match the exposure of a subject to 1200 mg mifepristone alonethan would 600 mg mifepristone in the presence of ketoconazole. Thus,these data also support the use of 900 mg mifepristone, and higher dosesas well, in the presence of ketoconazole.

For metabolite RU 42633, the 90% confidence intervals were within thestandard interval for C_(max) (geometric mean ratio 96.31%) and justoverlapping the lower bound of the standard interval for AUC₀₋₂₄(geometric mean ratio 91.34%). For metabolite RU 42698, confidenceintervals for both C_(max) and AUC₀₋₂₄ were overlapping and above thestandard interval (geometric mean ratio C_(max): 116.55%; AUC₀₋₂₄:118.18%). For metabolite RU 42848, the 90% confidence intervals wereoverlapping and below the standard interval for C_(max) (geometric meanratio 82.45%) and AUC₀₋₂₄ (ratio 81.43%).

RU 42698 is a relatively minor metabolite and comprises 9% of the totalsteady-steady AUC₀₋₂₄ of mifepristone, RU42633, RU42698, RU42848 aloneand 13% of the total steady-steady AUC₀₋₂₄ in the presence ofketoconazole. Therefore, the increase in RU 42698 AUC₀₋₁₄ in thepresence of ketoconazole is considered to be minor.

FIG. 1 illustrates the results of measurements of plasma levels ofmifepristone, RU42633, RU42698, and RU 42848. These measurements weremade prior to the daily administration of mifepristone to the subject;thus the mifepristone and metabolite concentrations are “trough”concentrations. These results show that trough concentrations ofmifepristone and RU42848 were increasing day-by-day through the start ofketoconazole administration (Day 13). This indicates that steady stateconditions may not have been attained at the time of ketoconazoleadministration (which began on day 13).

FIG. 2 shows the plasma concentration profile of mifepristone before andafter inhibition of CYP3A by ketoconazole. Applicant notes that the time0 values (pre-dose) differ by ˜500 ng/ml, a difference that ismaintained relatively constant throughout much of the 24-hour samplinginterval. Thus, if the daily increase in trough concentrations betweendays 7 and 12 persevered through day 17, an unknown fraction of theincreased AUC (and Cmax) between Day 12 and Day 17 could be due tofurther mifepristone administration rather than by an effect ofketoconazole alone. Thus, the values reported in Table 3 may overstatethe impact of CYP3A inhibition on exposure to mifepristone (andRU42848).

CONCLUSIONS: Co-administration of 600 mg mifepristone once daily with200 mg ketoconazole twice daily resulted in a mean increase in exposureto mifepristone of approximately 28% (C_(max): geometric mean ratio127.59% [90% CI: 116.66, 139.54]) and 38% (AUC₀₋₂₄: geometric mean ratio138.01% [90% CI: 127.12, 149.84]). These exposures are approximately 85%of those observed following the highest labeled dose of mifepristone(1200 mg daily).

The mean increase in exposure to the hydroxylated metabolite, RU 42698(approximately 70%), was somewhat greater than the increase in exposureto parent, resulting in exposure that was approximately 15 to 20% higherthan that following the highest labeled dose of mifepristone. Incontrast, co-administration with ketoconazole resulted in little changein exposure to the mono-demethylated metabolite, RU 42633, ordi-demethylated metabolite, RU 42848; exposure to these metabolites wassimilar to or slightly lower than exposure following the highest labeleddose.

The results presented in this example indicate that, with inhibition ofCYP3A (e.g., by co-administration of a strong CYP3A inhibitor such asketoconazole), a subject administered 900 mg mifepristone daily wouldexperience corresponding increases in mifepristone Cmax and AUC of27.59% and of 38.01%, respectively, which should yield systemicexposures similar in magnitude to those previously attained with 1200 mgdaily. Thus, the results of these measurements indicate that a subject,previously receiving a dose of 1200 mg mifepristone daily, may be safelyadministered a dose of 900 mg mifepristone daily when a strong CYP3Ainhibitor such as ketoconazole is added to the regimen. Similarly, theresults of these measurements indicate that a subject, previouslyreceiving a dose of 900 mg mifepristone daily, may be safelyadministered a dose of 600 mg mifepristone daily when a strong CYP3Ainhibitor such as ketoconazole is added to the regimen. In addition, theresults of these measurements indicate that a subject, previouslyreceiving a dose of 600 mg mifepristone daily, may be safelyadministered a dose of 300 mg mifepristone daily when a strong CYP3Ainhibitor such as ketoconazole is added to the regimen.

No deaths or SAEs were reported during the study. Two subjectsdiscontinued due to AEs (moderate hypertension in one subject andmoderate bilateral rash on the upper arms and thighs in the othersubject, both during the mifepristone-only treatment period). At leastone TEAE was reported in 55.6% (9 of 16) of the subjects duringtreatment with mifepristone alone, in 57.1% (8 of 14) of the subjectsduring the mifepristone/ketoconazole treatment period, and in 7.1% (1 of14) of the subjects during the washout period.

The majority of TEAEs were mild. Four subjects reported moderate TEAEs:three subjects during treatment with mifepristone alone (1 eachreporting hypertension, rash, and vomiting) and 1 subject duringtreatment with mifepristone/ketoconazole (headache). All four moderateAEs were considered possibly or probably related to mifepristonetreatment. Only 1 of the moderate AEs was considered to be possiblyrelated to ketoconazole treatment. No severe TEAEs were reported.

Three subjects had elevated laboratory test results that were reportedas drug-related TEAEs. Mildly elevated liver enzymes were noted for onesubject starting on the morning of Day 14, and mildly elevatedcreatinine levels were noted for two subjects starting on the morning ofDay 14. Dosing was not interrupted for any of the subjects, and theevents resolved without sequelae.

No clinically significant effects of multiple-dose mifepristonetreatment with or without multiple-dose ketoconazole treatment wereobserved on hematology or urinalysis parameters, vital signs, or ECGs.

Example 4

The treatment regimen of a patient suffering from excess cortisol, whois receiving treatment with mifepristone at a daily dose of 1200 mgmifepristone, is altered to include concomitant administration of aneffective amount of ketoconazole and a reduced daily dose ofmifepristone, where the reduced daily dose of mifepristone is 900 mg, sothat the patient receives concomitant administration of ketoconazole andmifepristone. A measurement indicates that the liver function of thepatient is not significantly compromised by the concomitantadministration of ketoconazole and the reduced dose of mifepristone.

Example 5

The treatment regimen of a patient suffering from excess cortisol, whois receiving treatment with mifepristone at a daily dose of 900 mgmifepristone, is altered to include concomitant administration of aneffective amount of ketoconazole and a reduced daily dose ofmifepristone, where the reduced daily dose of mifepristone is 600 mg, sothat the patient receives concomitant administration of ketoconazole andmifepristone. A measurement indicates that the liver function of thepatient is not significantly compromised by the concomitantadministration of ketoconazole and the reduced dose of mifepristone.

Example 6

The treatment regimen of a patient suffering from excess cortisol, whois receiving treatment with mifepristone at a daily dose of 600 mgmifepristone, is altered to include concomitant administration of aneffective amount of ketoconazole and a reduced daily dose ofmifepristone, where the reduced daily dose of mifepristone is 300 mg, sothat the patient receives concomitant administration of ketoconazole andmifepristone. A measurement indicates that the liver function of thepatient is not significantly compromised by the concomitantadministration of ketoconazole and the reduced dose of mifepristone.

Example 7

The treatment regimen of a patient suffering from excess cortisol, whois receiving treatment with mifepristone at a daily dose of 1500 mgmifepristone, is altered to include concomitant administration of aneffective amount of ketoconazole and a reduced daily dose ofmifepristone, where the reduced daily dose of mifepristone is 1200 mg,so that the patient receives concomitant administration of ketoconazoleand mifepristone. A measurement indicates that the liver function of thepatient is not significantly compromised by the concomitantadministration of ketoconazole and the reduced dose of mifepristone.

All patents, patent applications, and publications identified herein arehereby incorporated by reference herein in their entireties.

TABLE 1 No. MIFEPRISTONE Mean Ratio Product Subjects Treatments Mean PKParameters (SD) Confidence ID/ Enter/ Age: Inter- AUC_(tot) AUC_(t)Interval Batch No. Study Study Complete Mean Sub- acting C_(max) T_(max)ng · h/ ng · h/ T_(1/2) C_(max) AUC_(total) (NME) Objective Design (M/F)Range strate Drug ng/mL h mL mL h ng/mL ng · h/mL Mifepris- Effect ofPhase 1, 12/12 28 MIFE 400 mg/d 3398   median 116939 38111 37.1  1.151.05 tone ketoconazole open-label, (12 M) 20-44 300 Keto   (6.77) 2.00(26850)  (8768)  (9.77) 0.81- 0.72- 300 mg 400 mg OD parallel mg 400 mg1.63 1.54 Tablet (or 200 mg group, C1 OD (C2/ (C2/C1) Keto 200 BID) onPK single MIFE 400 mg/d 4143   median 130925 40625 37.4  C1) mg of 300mg MIFE dose, 300 Keto (1736)   1.00 (60942) (16524) (18.5)  Tabletsingle dose multiple mg 200 mg Mifepristone keto doses, C2 BID givenfasted in healthy subjects MIFE = mifepristone, Keto = ketoconazole,AUC_(tot) = AUC_(total), AUC_(τ) = AUC₀₋₂₄ hours following single doseof MIFE C1 = Cohort 1, C2 = Cohort 2

TABLE 2 # MIFEPRISTONE Product Subjects Treatments Mean PK Parameters(SD) Mean Ratio ID/ Enter/ Age: Inter- AUC_(tot) AUC_(t) ConfidenceInterval Batch # Study Study Complete Mean Sub- acting C_(max) T_(max)ng · h/ ng · h/ T_(1/2) C_(max) AUC_(t) (NME) Objective Design (M/F)Range strate Drug ng/mL h mL mL h ng/mL ng · h/mL Mifepris- Effect ofPhase 1, 12/10 29.8 MIFE 2700 median NC^(a) 37734 1.19 1.25 tone 400 mgopen-label, (12 M) 20-43 300  (534) 3.0 (11905) 0.93-1.53 0.88-1.76 300mg single dose of parallel mg/d C1 C1 Day C1 Day Tablet ketoconazolegroup, Day 7 8/Day 7 8/Day 7 Keto on PK an 8 crossover MIFE 400 mg 3240median NC^(a) 47357 84.9 1.39 1.28 200 mg day regimen within 300 Keto (760) 2.1 (17239) (46.6) 1.13-1.70 1.09-1.49 Tablet of 300 group withmg/d C1 single C2 Day C2 Day mg OD multiple Day 8 dose 8/Day 7 8/Day 7Mifepristone MIFE MIFE 3818 median NC^(a) 54174 1.42 1.48 (or 600dosees, 600  (703) 4.0  (7305) 1.13-1.78 1.13-1.94 mg OD and single mg/dC2 Day 7 Day 7 Mifepristone) keto dose, Day 7 C2/C1 C2/C1 given with inhealthy MIFE 400 mg 5264 median NC^(a) 69112 96.2 1.65 1.52 moderate fatsubjects 600 Keto  (795) 4.0  (9077) (45.4) 1.30-2.08 1.14-2.02 (34%)mg/d C2 single Day 8 Day 8 breakfast Day 8 dose C2/C1 C2/C1 MIFE =mifepristone, Keto = ketoconazole C1 = Cohort 1, C2 = Cohort 2 AUC_(τ) =AUC0-24 hours Following Day 7 or Day 8 dose of MIFE ^(a)AUC_(tot) =AUC_(total), not computed (NC) for multiple dosing

TABLE 3 Effects of Co-Administration with Ketoconazole on Mifepristoneand Metabolites Test: Day 17-600 mg mifepristone OD + 200 mgKetoconazole BID Reference: Day 12-600 mg mifepristone OD Ratio % Test/Lower Upper Analyte Parameter N Reference 90% CI 90% CI MifepristoneC_(max) 13 127.59 116.66 139.54 AUC₀₋₂₄ 13 138.01 127.12 149.84 RU 42633C_(max) 13 105.73 95.92 116.54 AUC₀₋₂₄ 13 102.33 94.31 111.03 RU 42698C_(max) 13 169.13 156.36 182.94 AUC₀₋₂₄ 13 166.86 155.06 179.57 RU 42848C_(max) 13 95.48 90.82 100.38 AUC₀₋₂₄ 13 94.88 91.33 98.56

TABLE 4 Effects of Co-Administration with Mifepristone on KetoconazoleTest: Day 17-600 mg mifepristone OD + 200 mg Ketoconazole BID Reference:Day-1-200 mg Ketoconazole Single Dose Ratio % Lower Upper Parameter NTest/Reference 90% CI 90% CI C_(max) 14 252.71 214.85 297.26 AUC 14365.36 333.78 399.93

TABLE 5 Cross-study Comparison of Exposure to Mifepristone andMetabolites Test: Present Study Day 17-600 mg mifepristone OD + 200 mgKetoconazole BID Reference: Historic Study Day 7-1200 mg mifepristone ODalone Ratio % Lower Upper Analyte Parameter Test/Ref 90% CI 90% CIMifepristone C_(max) 84.64 72.92 98.23 AUC₀₋₂₄ 87.27 74.72 101.94 RU42633 C_(max) 96.31 80.83 114.75 AUC₀₋₂₄ 91.34 76.95 108.43 RU 42698C_(max) 116.55 97.47 139.38 AUC₀₋₂₄ 118.18 97.90 142.66 RU 42848 C_(max)82.45 70.31 96.70 AUC₀₋₂₄ 81.43 69.71 95.11 All doses given within 30minutes after typical (34%) fat meal

The invention claimed is:
 1. A method of controlling hyperglycemiasecondary to hypercortisolism in a patient with endogenous Cushing'ssyndrome, said patient taking an original once-daily dose of 1200 mg perday of mifepristone, the method comprising the steps of: reducing theoriginal once-daily dose to an adjusted once-daily dose of 900milligrams (mg) per day of mifepristone, and administering the adjustedonce-daily dose of 900 mg per day of mifepristone and a strong CYP3Ainhibitor to the patient, wherein said strong CYP3A inhibitor isselected from the group consisting of ketoconazole, itraconazole,nefazodone, ritonavir, nelfinavir, boceprevir, clarithromycin,conivaptan, lopinavir, saquinavir, telaprevir, cobicistat,troleandomycin, tipranivir, and paritaprevir.
 2. The method of claim 1,wherein said strong CYP3A inhibitor is selected from the groupconsisting of nefazodone, ritonavir, nelfinavir, boceprevir,clarithromycin, conivaptan, lopinavir, saquinavir, telaprevir,cobicistat, troleandomycin, tipranivir, and paritaprevir.
 3. The methodof claim 1, wherein said CYP3A inhibitor is ketoconazole.
 4. The methodof claim 2, wherein said CYP3A inhibitor is clarithromycin.
 5. Themethod of claim 1, wherein said CYP3A inhibitor is itraconazole.
 6. Amethod of controlling hyperglycemia secondary to hypercortisolism in apatient with endogenous Cushing's syndrome, said patient taking a strongCYP3A inhibitor selected from ketoconazole, itraconazole, nefazodone,ritonavir, nelfinavir, indinavir, boceprevir, clarithromycin,conivaptan, lopinavir, posaconazole, saquinavir, telaprevir, cobicistat,troleandomycin, tipranivir, paritaprevir and voriconazole, the methodcomprising administering to the patient a once-daily dose ofmifepristone of 900 milligrams (mg) per day.
 7. The method of claim 6,wherein said CYP3A inhibitor is ketoconazole.
 8. The method of claim 6,wherein said CYP3A inhibitor is troleandomycin.
 9. The method of claim6, wherein said CYP3A inhibitor is itraconazole.
 10. The method of claim6, wherein said CYP3A inhibitor is clarithromycin.
 11. The method ofclaim 6, wherein said CYP3A inhibitor is lopinavir, ritonavir, or both.12. The method of claim 6, wherein said CYP3A inhibitor is nelfinavir.13. The method of claim 6, wherein said CYP3A inhibitor is cobicistat.14. The method of claim 6, wherein said CYP3A inhibitor is nefazodone.